Information

How does the flow of ions along voltage-gated channels lead to nerve conduction along axons?


Let's say the axon lies along the x axis, and voltage-gated sodium channels lie parallel to the y axis. When a channel is opened, sodium ions will flow along the y direction into the cellular fluid. My question is, how does this flow of ions in the y direction cause a flow of electric current in an entirely different direction (i.e., the x direction along the axon)?

Both layman and technical explanation would be appreciated.


The flow of current during action potential generation is perpendicular to the axon length. The channels that transmit ions in neurons are often voltage-gated. Voltage-gated Na+ channels (VGSCs) open when the membrane depolarizes. So when excitatory neurotranmitters (e.g., glutamate) open up channels (e.g., AMPA receptors) in the dendritic region, anions (e.g., Na+) flow in. The ensuing membrane depolarization opens up VGSCs in the axon hillock, that subsequently opens VGSCs adjacently in the axon, that opens up VGSCs a little further up in the axon etc etc. Hence, while the flow of Na+ is perpendicular to the axonal membrane, the net effect is a wave of VGSCs opening up along the axon length. With some delay, voltage-gated K+ channels open that allow K+ to flow in, repolarizing the membrane, preparing the neuron for another action potential (fig. 1).


Fig. 1. Action potential mediated by step wise activation of voltage-gated ion channels. Source: Human Medical Physiology

Hence, although neuronal ion fluxes and networks can be modeled by electric currents flowing in electronic circuitry (Fig. 2), nerve conduction is not anything like it. Current flow in electronic circuits is a flow of electrons. In action potentials in neurons it is ions that carry the transported charge.

.
Fig. 2. Hodgkin & Huxley's axon model. The power sources are the electric gradients of Na+, K+ and a leak current source. The conductances are represented by those same ions. The cell membrane is modeled by a capacitor. Source: Bonabi et al. (2014)

Reference
- Bonabi et al., Front Neurosci (2014)


Lesson Explainer: The Nerve Impulse Biology

In this explainer, we will learn how to explain how a resting potential is maintained and describe the electrical and chemical changes that occur during an action potential.

The human body contains over seven trillion nerves. Each signal these nerves send can travel at rapid speeds of up to 120 metres (almost 400 feet ) every second! This amazing evolutionary development allows us to think quickly and even act without thinking, to respond to our environment and aid our survival.

A neuron is a specialized cell found within the nervous system. Neurons’ function is to transmit information in the form of an electrical signal: a nerve impulse.

A nerve impulse is initiated by a stimulus, that is, a change in the internal or external environment. This stimulus triggers a receptor to send a nerve impulse to our central nervous system (CNS). The CNS, consisting of the brain and spinal cord, processes the information. Nerve impulses are then transmitted from the CNS to different organs that allow us to react to the stimulus appropriately. For example, a stimulus of touching a hot object will cause a series of nerve impulses to contract muscles in your arm to pull your hand away.

Definition: Neuron

A neuron is a specialized cell that transmits nerve impulses.

Let’s look at the structure of a neuron. Neurons come in many shapes and sizes however, most of them have a similar basic structure. Figure 1 shows an example of a neuron.

The nerve impulse first starts at the dendrites, then arrives at the cell body, which contains the nucleus of the neuron. The red arrows in Figure 1 show the path that the nerve impulse will take from the cell body and along the threadlike part of the neuron called an axon. Some neurons, like the one in Figure 1, have an insulating layer surrounding the axon called a myelin sheath. There are small gaps in the myelin sheath, called nodes of Ranvier, that play an important role in increasing the speed of a nerve impulse.

Key Term: Axon

An axon is the long threadlike part of a neuron along which nerve impulses are conducted.

To initiate and propagate a nerve impulse, a neuron must be excitable. What makes neurons electrically excitable?

The cytoplasm of neurons and the extracellular space are different fluids with different chemical compositions. As a consequence, they do not contain the same amounts of charged ions. There is normally an excess of positive charges in the extracellular space as we will see later in this explainer. This creates an electric tension, or potential, between both sides of the membrane, with the positive ions outside attracted by the negatively charged cytoplasm. In physics, this kind of electric force is called a voltage. The membrane is said to be polarized because of this difference of potential. Potentially, if there was a hole or a channel in the membrane, the positive ions would move freely inside until their concentration and charges equilibrate on both sides of the membrane.

The difference between the voltage inside the neuron’s cytoplasm and the extracellular space is called the membrane potential.

Key Term: Membrane Potential

The membrane potential, or potential difference, is the difference in electrical potential between the interior and exterior of a neuron.

When a neuron is not transmitting a nerve impulse, it is said to be at rest, and the membrane has its resting potential. The mechanism by which the resting potential is maintained is summarized in Figure 2.

Key Term: Resting Potential

The resting potential is the potential difference across the membrane of a neuron at rest (around

The resting potential is maintained through active transport by proteins embedded in the neuron membrane called sodium–potassium pumps. The sodium–potassium pump moves positively charged sodium (

) ions across the membrane using ATP energy. It requires energy, as sodium and potassium are being transported against their concentration gradients from an area of low concentration to an area of high concentration. For every three sodium ions pumped out of the neuron, two potassium ions are pumped in. This makes the voltage in the extracellular space more positive than the neuron’s cytoplasm. It also increases the concentration of potassium ions inside the neuron. In fact, the concentration of sodium ions is 10x–15x higher outside the neuron than inside, and the concentration of potassium is 30x higher inside the cell than outside!

The constant activity of sodium–potassium pumps plays a vital role in keeping neurons excitable. Ouabain, a plant-derived poison, has been used for several thousand years by West African tribes to make poisonous arrows. Ouabain is a potent blocker of the sodium–potassium pump as it attacks the nervous system, and one poisonous arrow is enough to rapidly kill any hunted animal, even an elephant.

Key Term: Sodium–Potassium Pump

The sodium–potassium pump maintains the resting potential of the axon membrane by transporting three sodium ions out and two potassium ions into the neuron.

The activity of the pump creates an imbalanced distribution of

across the membrane, with a higher concentration of

inside the neuron than outside and a higher concentration of

outside than inside. At rest, the membrane allows a minimal flow of these ions and remains 40x more permeable to

passively diffuses through pores called “leak” channels specific to these ions, moving down their concentration gradient from an area of high to low

concentration in the extracellular space.

The “leak” channels are always open, so the membrane is permeable to

remains forty times smaller. This net flow of ions ultimately lowers the membrane potential, as the outside of the cell becomes more positively charged.

Key Term: “Leak” Channels

“Leak” channels, or potassium ion channels, are always open making the neuron membrane permeable to potassium ions.

There are also negatively charged ions, such as chloride, and negatively charged proteins in a higher concentration inside the neuron. With the action of the sodium–potassium pump and “leak” channels, this contributes to making the extracellular space outside the neuron more positively charged than the cytoplasm inside the neuron. The membrane is polarized, achieving a resting potential of around

Example 1: Describing the Status of Ion Channels in Maintenance of the Resting Potential

When the resting potential is being maintained, are potassium ion channels (leak channels) open or closed?

Answer

When the neuron is at rest, the extracellular space is more positively charged than the neuron’s cytoplasm. The membrane is polarized, and the membrane potential is around

The resting potential is maintained primarily through active transport by proteins embedded in the neuron membrane called sodium–potassium pumps. The sodium–potassium pump moves positively charged sodium (

) ions across the membrane using ATP. It requires energy, as

are being transported against their concentration gradients from an area of low concentration to an area of high concentration. For every

ions that are pumped out of the neuron,

ions are pumped in. This makes the voltage in the extracellular space more positive than the neuron cytoplasm. It also increases the concentration of

concentration inside the neuron,

will also “leak” across the neuron membrane out of the cytoplasm into the extracellular space. It passively diffuses through pores called “leak” channels specific to

, moving down its concentration gradient from an area of high to low

concentration. “Leak” channels are always open, so the membrane is permeable to

. This lowers the membrane potential, as the outside of the cell is becoming more positively charged, achieving the resting potential of

Therefore, when resting potential is maintained, the potassium ion channels (leak channels) are open.

When the neuron is not at rest, it is conducting a nerve impulse called an action potential.

Action potentials are electrical signals that transmit information by the movement of charged ions across the membrane of a neuron as the action potential passes along it. This temporarily changes the potential difference at the particular point on the neuron where ions are moving.

The main stages of an action potential are

  1. depolarization,
  2. repolarization,
  3. Hyperpolarization,
  4. a brief refractory period during which another action potential cannot be generated.

The movement of ions in depolarization and repolarization is summarized in Figure 3.

Key Term: Action Potential

An action potential is the transient change in the potential difference across the neuron membrane when stimulated (approximately

Let’s look at depolarization first.

Depolarization is when the membrane potential at one point on the neuron reverses from negative to positive. This is initially caused by the activation of chemical receptors at synapses located at the dendrites of a neuron. The activation of these receptors triggers the opening of voltage-gated

channels that were previously shut, making the membrane more permeable to

diffuses into the neuron cytoplasm as it is less concentrated there than in the extracellular space due to the action of the sodium–potassium pump. The increased concentration of

makes the neuron cytoplasm less negatively charged as you can see in Figure 4. The increased positivity of the membrane potential causes more voltage-gated

channels to open. This means that

diffuses into the neuron at a faster rate, which continues until the membrane potential reaches a value of around

Key Term: Depolarization

Depolarization is a change in the membrane potential at one point in a neuron from negative to positive.

Key Term: Voltage-Gated Ion Channels

Voltage-gated ion channels are those that open and close in response to changes in the membrane potential of the cell and, as a result, enable a flow of ions across a membrane.

When the membrane potential has reached

channels close, and voltage-gated

can no longer enter the neuron.

is more concentrated in the neuron cytoplasm than in the extracellular space due to the action of the sodium–potassium pump, so

can now diffuse out. This lowers the membrane potential, and the neuron cytoplasm again becomes less positively charged than the extracellular space. This is called repolarization, as you can see in Figure 5.

Key Term: Repolarization

Repolarization is a change in the membrane potential at one point in a neuron from positive back to negative.

diffuses out of the neuron when the voltage-gated

channels open that the membrane potential temporarily becomes even more negative than its resting potential. This is called hyperpolarization.

Hyperpolarization causes the voltage-gated

channels to close, and the sodium–potassium pump resets the membrane to its resting potential. You can see this occurring in the final stage of Figure 3. This period of time is called the refractory period, during which no more action potentials can be generated as the voltage-gated

channels remain closed. Refractory periods last a very short time, usually between 0.001 and 0.003 seconds !

Key Term: Hyperpolarization

Hyperpolarization is a change in the membrane potential at one point in a neuron to more negative than its original resting potential.

Key Term: Refractory Period

The refractory period is a brief period immediately following an action potential during which a neuron is unresponsive to further stimulation and therefore cannot generate another action potential.

Example 2: Stating the Sequence of Stages in an Action Potential

The diagram provided shows the stages of an action potential, with each stage assigned a number. State the correct sequence of numbers.

Answer

An action potential is a change in the electrical potential of the neuron membrane as the nerve impulse passes along the neuron. Its main stages are depolarization, repolarization, hyperpolarization, and a brief refractory period.

Depolarization is when the electrical charge at one point on the neuron membrane reverses from negative to positive. This is caused by energy from a stimulus triggering the opening of voltage-gated

diffuses into the neuron cytoplasm. The increased concentration of

makes the neuron cytoplasm less negatively charged, which causes more voltage-gated

diffuses into the neuron at a faster rate until the membrane potential reaches around

can no longer enter the neuron. Voltage-gated

can diffuse out of the neuron cytoplasm. This lowers the membrane potential, and the neuron cytoplasm again becomes less positively charged than the extracellular space. This is called repolarization.

diffuses out of the neuron that the membrane potential becomes even more negative than its resting potential. This is called hyperpolarization, and it causes the voltage-gated

channels to close. The sodium–potassium pump resets the membrane to its resting potential in a period of time called the refractory period. During the refractory period, no more action potentials can be generated as the voltage-gated

Therefore, the correct sequence of events in an action potential is 4, 2, 6, 1, 5, 3.

Let’s look at the graph in Figure 6 showing how the membrane potential changes during an action potential.

  1. In stage 1, the resting potential is being maintained at stage 1, with the sodium–potassium pump and “leak” channels keeping the membrane potential at around

channels to open at stage 2, depolarizing the membrane to

channels open. Stage 3 shows repolarization of the membrane, as

Example 3: Describing the Events of an Action Potential

The graph provided shows how the potential difference across an axon membrane changes during the course of an action potential. What is happening during stage 2?

Answer

The resting potential is being maintained at stage 1, with the sodium–potassium pump keeping the membrane potential at around

mV . A stimulus has caused voltage-gated

channels to open at stage 2, depolarizing the membrane to

channels open. Stage 3 shows repolarization of the membrane, as

diffuses out of the axon. Stage 4 shows hyperpolarization of the membrane, overshooting the resting potential. Following this refractory period, the resting potential is reset in stage 5, returning the membrane potential to

Therefore, at stage 2, a stimulus has triggered the opening of voltage-gated sodium ion channels, and sodium ions depolarize the membrane.

Example 4: Describing the Events of an Action Potential

The graph provided shows how the potential difference across an axon membrane changes during the course of an action potential. What is happening during stage 3?

Answer

The resting potential is being maintained at stage 1, with the sodium–potassium pump keeping the membrane potential at around

mV . A stimulus has caused voltage-gated

channels to open at stage 2, depolarizing the membrane to

channels open. Stage 3 shows repolarization of the membrane, as

diffuses out of the axon. Stage 4 shows hyperpolarization of the membrane, overshooting the resting potential. Following this refractory period, the resting potential is reset in stage 5, returning the membrane potential to

Therefore, at stage 3, voltage-gated potassium ion channels open, and potassium ions diffuse out of the axon.

An action potential is then propagated from one end of the neuron’s axon to the other, in one direction only. This propagation is referred to as a wave of depolarization.

This is because as one section of the axon’s membrane depolarizes, positively charged

moves into the axon cytoplasm, as you can see in the green section of stage 1 in Figure 7.

Voltage-gated sodium channels next to the initial site of depolarization get activated so that sodium diffuses along the axon to depolarize the next section as you can see in stage 2 in Figure 8. This triggers voltage-gated

channels in this next section to open, and the membrane at this point becomes fully depolarized.

The wave of depolarization can only travel in one direction, as the section behind the depolarized section in stage 3 is repolarizing, as you can see in Figure 9. The voltage-gated

diffuses out of the axon, making it more negative than the extracellular space, and the membrane hyperpolarizes. During this refractory period, the voltage-gated

channels remain shut, so no

can move into the axon and the

in the wave of depolarization cannot diffuse backward.

The strength of a stimulus determines whether an action potential will be generated. If the stimulus passes a threshold value, it will always trigger an action potential. If the stimulus does not pass this value, no action potential will be generated. Therefore, action potentials are called all-or-nothing responses.

Though the action potential will always be the same size, if a stimulus is stronger, the frequency of action potentials will be higher and so more will be generated per unit time.

Key Term: The All-or-Nothing Principle

The all-or-nothing principle states that if a stimulus is large enough to pass a threshold value, an action potential of the same size will always be generated. If the stimulus is not large enough to pass this value, no action potential will be generated.

Three factors affect the speed of transmission of an action potential.

At higher temperatures, ions diffuse faster as they have more kinetic energy. This increases the speed of the action potential. At temperatures above

, however, proteins such as the sodium–potassium pump start to denature, which causes transmission rate to drop.

The diameter of the axon also affects the speed of an action potential. The larger the diameter, the faster the transmission, as the diffusing ions encounter less resistance. This is like if lots of people were trying to walk along a wide corridor, it would be much easier than the same number of people walking along a narrow one!

Whether or not an axon is myelinated also affects the speed of transmission. Myelinated axons conduct nerve impulses faster than nonmyelinated axons. The speed of propagation of a nonmyelinated axon is around 12 metres per second , whereas propagation along a myelinated axon can reach up to 140 metres per second !

The voltage-gated ion channels are only found in the nodes of Ranvier in myelinated axons, so depolarization can only occur at these points. This means that the action potential “jumps” from one node to the next as represented by the pink arrows in Figure 10. This process is called saltatory conduction, from the Latin word meaning “leap,” and it speeds up the transmission as less time is taken in opening and closing ion channels.

Comparatively, lots of ion channels are opening and closing in the nonmyelinated axon in Figure 10, so the speed of propagation of the action potential is much slower.

Key Term: Saltatory Conduction

Saltatory conduction describes how action potentials propagate along a myelinated axon by “jumping” from one node of Ranvier to the next, increasing the speed of conduction compared to nonmyelinated axons.


Action Potentials

Muscle and nerve cells are excitable cells, meaning that the resting membrane potential changes in response to stimuli that activate gated ion channels. The opening and closing of gated channels can change the permeability characteristics of the cell membrane and hence change the membrane potential.


The channels responsible for the action potential are voltage-gated Na + and K + channels. When the cell membrane is at rest, the voltage-gated channels are closed (figure 8.8, step 1). When a stimulus is applied to a muscle cell or nerve cell, following neurotransmitter activation of chemically gated channels, Na + channels open very briefly, and Na + diffuses quickly into the cell (figure 8.8, step 2). This movement of Na + , which is called a localcurrent, causes the inside of the cell membrane to become posi-tive, a change called depolarization. This depolarization results in a local potential. If depolarization is not strong enough, the Na + channels close again, and the local potential disappears without being conducted along the nerve cell membrane. If depolariza-tion is large enough, Na + enters the cell so that the local potential reaches a threshold value. This threshold depolarization causes voltage-gated Na + channels to open. Threshold is most often reached at the axon hillock, near the cell body. The opening of these channels causes a massive, 600-fold increase in membrane permeability to Na + . Voltage-gated K + channels also begin to open. As more Na + enters the cell, depolarization occurs until a brief reversal of charge takes place across the membrane—the inside of the cell membrane becomes positive relative to the outside of the cell membrane. The charge reversal causes Na + channels to close and more K + channels to open. Na + then stops entering the cell, and K + leaves the cell (figure 8.8, step 3). This repolarizes the cell membrane to its resting membrane potential. Depolarization and repolarization constitute an action potential (figure 8.9). At the end of repolarization, the charge on the cell membrane briefly becomes more negative than the resting mem-brane potential this condition is called hyperpolarization. The elevated permeability to K + lasts only a very short time.


In summary, the resting membrane potential is set by the activity of the leak channels. On stimulation, chemically gated channels are opened and initiate localpotentials. If sufficiently strong, the local potentials activate voltage-gated channels to initi-ate an action potential.

Action potentials occur in an all-or-none fashion. That is, if threshold is reached, an action potential occurs if the threshold is not reached, no action potential occurs. Action potentials in a cell are all of the same magnitude—in other words, the amount of charge reversal is always the same. Stronger stimuli produce a greater frequency of action potentials but do not increase the size of each action potential. Thus, neural signaling is based on the number of action potentials.

Action potentials are conducted slowly in unmyelinated axons and more rapidly in myelinated axons. In unmyelinated axons, an action potential in one part of a cell membrane stimulates local currents in adjacent parts of the cell membrane. The local cur-rents in the adjacent membrane produce an action potential. By this means, the action potential is conducted along the entire axon cell membrane. This type of action potential conduction is called continuous conduction (figure 8.10).


In myelinated axons, an action potential at one node of Ranvier causes a local current to flow through the surrounding extracellular fluid and through the cytoplasm of the axon to the next node, stimulat-ing an action potential at that node of Ranvier. By this means, action potentials “jump” from one node of Ranvier to the next along the length of the axon. This type of action potential conduction is calledsaltatory (sal ′ tă-tōr-ē to leap) conduction (figure 8.11).


Saltatory conduction greatly increases the conduction velocity because the nodes of Ranvier make it unnecessary for action potentials to travel along the entire cell membrane. Action potential conduc-tion in a myelinated fiber is like a child skipping across the floor, whereas in an unmyelinated axon it is like a child walking heel to toe across the floor.

Medium-diameter, lightly myelinated axons, characteristic of autonomic neurons, conduct action potentials at the rate of about 3–15 meters per second (m/s), whereas large-diameter, heavily myelinated axons conduct action potentials at the rate of 15–120 m/s. These rapidly conducted action potentials, carried by sensory and motor neurons, allow for rapid responses to changes in the external environment. In addition, several hundred times fewer ions cross the cell membrane during conduction in myelinated cells than in unmyelinated cells. Much less energy is therefore required for the sodium-potassium pump to maintain the ion distribution.


Types of synapses

There are two types of synapses:

Electrical synapses

In electrical synapses, two neurons are connected through channel proteins for transmitting a nerve impulse. The nerve impulse travels across the membrane of the axon in the form of an electrical signal. The signal is transmitted in the form of ions and therefore it is much faster than chemical synapses.

In electrical synapses, the synaptic gap is about 0.2nm which also favors faster nerve impulse conduction.

Chemical synapses

CNS and Nerve Impulse

Neurons help in transmitting signals in the form of a nerve impulse from the Central nervous system to the peripheral body parts. Neurons are a complex network of fibers that transmit information from the axon ending of one neuron to the dendrite of another neuron. The signal finally reaches the target cell where it shows a response.

In conducting nerve impulse, the following play a major role:

  • Axon- Helps in the propagation of nerve impulses to the target cell.
  • Dendrites- Receive the signals from the axon ends.
  • Axon Ending- Acts as a transmitter of signals.

Axon plays a major role in the process by transmitting signals in the form of nerve impulses via synapses to the target cells. The neuron is responsible for transferring signals to three target cells:

And this results in the contraction of muscle, secretion by glands and helps neurons to transmit action potential.


How does the flow of ions along voltage-gated channels lead to nerve conduction along axons? - Biology

1) To understand the properties of these channels using channel specific drugs like Tetradotoxin (TTX) and Tetraethylammonium (TEA).

2) To understand the role of selective blocking and complete blocking on action potential generation.

Tetradotoxin: An alkaloid neurotoxin, produced by certain species of puffer fish, tropical frogs, and salamanders, that selectively blocks voltage-sensitive Na+ channels eliminates the initial Na+ current measured in voltage clamp experiments.

Tetraethlyammonium: A quaternary ammonium compound that selectively blocks voltage-sensitive K+ channels eliminates the delayed K+ current measured in voltage clamp experiments.

Action potentials are known to be the source of communication transmitted from one part of the body to another through neurons, which are commonly represented as electrical signals. The main principle underlying this mechanism is regulated by ionic channels through selective permeability of ions with respect to the concentration gradient at a specific point of time, calculated by the amount of ions present outside and inside of the cell. From earlier exercise explanation (refer Modeling Action Potentials) it has become clear that depolarization occurs through fast Na+ channels and repolarization is through delayed rectifier K+ channels. With sufficient stimulus strength, the voltage of the neuronal membrane rapidly increases due to the influx of sodium ions thereby facilitating activation of feedback loop and decreases due to outflow of potassium ions. Flow of sodium ions into nerve cells is a necessary step in the conduction of nerve impulses in excitable nerve fibers and along axons. Understanding the properties of these ionic channels became a necessity to understand the underlying dynamics. Many postulates have been considered until mid-1960s which included permeation, binding and migration, passage through carriers, flow through pores, etc.

Around mid-1960s, Katz and Ricardo Miledi used Tetradotoxin (TTX) and Tetraethylammonium (TEA) in their attempt to study the properties of these channels. It is known that pharmacological experiments with molecules such as TTX and TEA, shown in Figure 1 provided the key to study channels as discrete entities (Kandel, 2000). Selective blocking of one of the channels enabled us to study the behavior and properties of the ionic channels as the action potentials result mainly due to the intricate interplay between sodium and potassium channels. Thereby, blocking one of the channels would enable us to study the properties of another channel.

Main principle of pharmacological class of drugs is that they are highly selective and they would bind to specific molecular components of specific regions of the neuron. Though many drugs and toxins exist to study these ion channels, we restrict our study to Tetradotoxin (TTX) and Tetraethlammonium (TEA) in this exercise as they are widely employed. Using these two agents (Tetradotoxin (TTX) and Tetraethlyammonium (TEA)), we can test our understanding of the ionic mechanisms of the action potential.

Figure 1: Left side of the above figure shows molecular structure of TTX and right side shows molecular structure of TEA.

Tetradotoxin (TTX), isolated from the Japanese puffer fish is a virulent poison known to cause respiratory paralysis, blocks conduction of nerve and muscle through its rather selective inhibition of the sodium-carrying mechanism. This drug should be administered at very low dose levels typically of the order 10-7 to 10-9 (micro-molecular concentrations) which acts in a reversible manner. It means that after the administration of the drug, the actual property of the channels can be reversed by washing with normal medium (early studies used sea water). The recovery can be partial or complete depending on the precision of the process applied. Experimental studies with voltage-clamp helped to show the suppression of the rise of sodium and potassium conductance normally occurring upon depolarization. TTX is known to block excitability through its selective inhibition of the sodium-carrying system without affecting the potassium-carrying system (Nakajima et al., 1962 Narahashi et al., 1960). From one of the studies conducted by Narahashi 1964a, this view is supported by the finding that maximum rate of rise of the action potential, which is indicative of the inward sodium current during activity is decreased much faster than is the rate of fall during the course of TTX block. This did not affect the resting potential. TTX much larger than the sodium ion, acts like a cork in a bottle, preventing the flow of sodium until it slowly diffuses off. TTX competes with the hydrated sodium cation and enters the Na+ channel where it binds. It is proposed that this binding results from the interaction of the positively charged guanidine group on the TTX and negatively charged carboxylate groups on side chains in the mouth of the channel.

Why this doesn&rsquot have any effect on the host (Puffer fish)?

Sodium ion channel in the host must be different than that of the victim. The toxin might not have any effect, probably due to difference in the amino acid sequence of sodium channel. Protein of the sodium ion channel has undergone a mutation that changes the amino acid sequence making the channel insensitive to tetrodotoxin. The spontaneous mutation that causes this structural change is beneficial to the puffer fish because it allowed it to incorporate the symbiotic bacteria and utilize the toxin it produces to its best advantage. A single point mutation in the amino acid sequence of the sodium-ion channel in this species renders it immune from being bound and blockaded by TTX.

Tetraethylammonium(TEA) is synthesized from bromopentacarbonylrhenium by heating it with tetraethylammonium bromide in diglyme. It is a potassium-selective ion channel blocker. From the diagram you can observe that initial phase of the action potentials is identical, but note that it is much longer and does not have an after-hyperpolarization. There is a repolarization phase, but now the repolarization is due to the process of Na+ inactivation alone. There is no change in the resting potential. The channels in the membrane that endow the cell with the resting potential are different from the ones that are opened by voltage. They are not blocked by TEA. TEA only affects the voltage-dependent changes in K+ permeability. Perfusion of an axon by TEA also increases the duration of a propagated action potential but has no effect on its speed of propagation. It only affects only the fall time of the action potential. Bath application of TEA (1-10 mM) depolarized the resting potential, prolonged the action potential and increased the amplitude and duration of the ensuing passive depolarizing after-potential (DAP) in a dose-dependent and reversible manner. TEA increased the axonal input resistance and the slow time constant of the passive voltage response, not only in depolarized axons, but also in resting and hyperpolarized axons. TEA&rsquos effects on the resting potential and action potential usually approached a steady state within 5 mins, whereas TEA&rsquos effects on input resistance and on the amplitude and time course of the DAP increased progressively for 10-15 min or more, and persisted for 10-15 after removal of TEA from the bath.

TEA increases the duration of the action potential (Schmidt & Stampfli, 1966) by blocking depolarization-activated delayed rectifier K+ channels in the nodal axolemma. A motor nerve terminal stimulated in the presence of TEA releases more transmitter (Katz & Miledi, 1969 Benoit & Mambrini, 1970), and may discharge repetitive action potentials (Koketsu, 1958 Payton & Shand, 1966). TEA is also known to reverse the action of drugs such as tubocurarine, a non-depolarizing blocker. TEA evokes more release of the neurotransmitter and thus it will reverse the competitive antagonistic block of any drugs belonging to the curare family.


Along with these drugs, another drug by name Pronase is also studied with the help of neuron simulator which plays an important role in blocking sodium channel inactivation (acts as an antagonist to TTX). It&rsquos been extensively used to analyze the kinetics of sodium channel activation.


How does the flow of ions along voltage-gated channels lead to nerve conduction along axons? - Biology

1. Resting membrane potential depends on:

1. differential distribution of ions across the axon membrane.

2. the opening of voltage-gated calcium channels.

3. active transport of ions across the membrane.

2. All of the following are associated with the myelin sheath EXCEPT:

1. faster conduction of nerve impulses.

2. nodes of Ranvier forming gaps along the axon.

3. increased magnitude of the potential difference during an action potential.

4. saltatory conduction of action potentials.

3. Which of the following is true with regard to the action potential?

1. All hyperpolarized stimuli will be carried to the axon terminal without a decrease in size.

2. The size of the action potential is proportional to the size of the stimulus that produced it.

3. Increasing the intensity of the depolarization increases the size of the impulse.

4. Once an action potential is triggered, an impulse of a given magnitude and speed is produced.

4. Which of the following correctly describes a difference between nerves and tracts?

1. Nerves are seen in the central nervous system tracts are seen in the peripheral nervous system.

2. Nerves have cell bodies in nuclei tracts have cell bodies in ganglia.

3. Nerves may carry more than one type of information tracts can only carry one type of information.

4. Nerves contain only one neuron tracts contain many neurons.

5. Which of the following accurately describes sensory neurons?

1. Sensory neurons are afferent and enter the spinal cord on the dorsal side.

2. Sensory neurons are efferent and enter the spinal cord on the dorsal side.

3. Sensory neurons are afferent and enter the spinal cord on the ventral side.

4. Sensory neurons are efferent and enter the spinal cord on the ventral side.

6. When a sensory neuron receives a stimulus that brings it to threshold, it will do all of the following EXCEPT:

2. transduce the stimulus to an action potential.

3. inhibit the spread of the action potential to other sensory neurons.

4. cause the release of neurotransmitters onto cells in the central nervous system.

7. When the potential across the axon membrane is more negative than the normal resting potential, the neuron is said to be in a state of:

8. Which of the following statements concerning the somatic division of the peripheral nervous system is INCORRECT?

1. Its pathways innervate skeletal muscle.

2. Its pathways are usually voluntary.

3. Some of its pathways are referred to as reflex arcs.

4. Its pathways always involve more than two neurons.

9. Which of the following is a function of the parasympathetic nervous system?

1. Increasing blood sugar during periods of stress

2. Dilating the pupils to enhance vision

3. Increasing oxygen delivery to muscles

4. Decreasing heart rate and blood pressure

10.Which of the following neurotransmitters is used in the ganglia of both the sympathetic and parasympathetic nervous systems?

11.In which neural structure are ribosomes primarily located?

12.An autoimmune disease attacks the voltage-gated calcium channels in the nerve terminal. What is a likely symptom of this condition?

1. Spastic paralysis (inability to relax the muscles)

2. Flaccid paralysis (inability to contract the muscles)

3. Inability to reuptake neurotransmitters once released

4. Retrograde flow of action potentials

13.A neuron only fires an action potential if multiple presynaptic cells release neurotransmitter onto the dendrites of the neuron. This is an example of:

4. inhibitory transmission.

14.A disease results in the death of Schwann cells. Which portion of the nervous system is NOT likely to be affected?

3. Autonomic nervous system

4. Parasympathetic nervous system

15.A surgeon accidentally clips a dorsal root ganglion during a spinal surgery. What is a likely consequence of this error?

1. Loss of motor function at that level

2. Loss of sensation at that level

3. Loss of cognitive function

Answers and Explanations

The polarization of the neuron at rest is the result of an uneven distribution of ions between the inside and outside of the cell. This difference is achieved through the active pumping of ions into and out of the neuron (using the Na + /K + ATPase). Voltage-gated calcium channels are important in the nerve terminal, where the influx of calcium triggers the fusion of vesicles containing neurotransmitter with the membrane, but not in maintaining resting membrane potential.

Myelin is a white lipid-containing material surrounding the axons of many neurons in the central and peripheral nervous systems. It is arranged on the axon discontinuously the gaps between the segments of myelin are called nodes of Ranvier, eliminating choice (B). Myelin increases the conduction velocity by insulating segments of the axon so that the membrane is permeable to ions only at the nodes of Ranvier, eliminating choice (A). The action potential jumps from node to node, a process known as saltatory conduction, eliminating choice (D). Action potentials are often described as being “all-or-nothing” the magnitude of the potential difference in an action potential is constant, regardless of the intensity of the stimulus. Thus, myelin does not affect the magnitude of the potential difference in an action potential, makingchoice (C) the correct answer.

As in the previous question, the action potential is often described as an all-or-nothing response. This means that, whenever the threshold membrane potential is reached, an action potential with a consistent size and duration is produced. Neuronal information is coded by the frequency and number of action potentials, not the size of the action potential, eliminating choices (B) and (C) and making choice (D) the correct answer. Hyperpolarizing (inhibitory) signals are not transmitted to the nerve terminal, eliminating choice (A).

Nerves are collections of neurons in the peripheral nervous system and may contain multiple types of information (sensory or motor) they contain cell bodies in ganglia. Tracts are collections of neurons in the central nervous system and contain only one type of information they contain cell bodies in nuclei.

Sensory neurons are considered afferent (carrying signals from the periphery to the central nervous system) and enter the spinal cord on the dorsal side. Motor neurons are considered efferent (carrying signals from the central nervous system to the periphery) and exit the spinal cord on the ventral side.

When a sensory neuron receives a signal that is strong enough to bring it to threshold, one can assume that the receptor becomes depolarized, allowing it to transduce the stimulus to an action potential. The action potential will then be carried by sensory neurons to the central nervous system, where the cell will release neurotransmitters. Therefore, among the given choices, the only incorrect statement is found in choice (C). If a receptor is stimulated, it will promote the spread of the action potential to postsynaptic sensory neurons in the spinal cord, which can send the signal toward the brain.

When the potential across the axon membrane is more negative than the normal resting potential, the neuron is referred to as hyperpolarized. Hyperpolarization occurs right after an action potential and is caused by excess potassium exiting the neuron.

The somatic division of the peripheral nervous system innervates skeletal muscles and is responsible for voluntary movement. Some of the pathways in this part of the nervous system are reflex arcs, which are reflexive responses to certain stimuli that involve only a sensory and a motor neuron. These neurons synapse in the spinal cord and do not require signaling from the brain. The pathways of the somatic division can involve two, three, or more neurons, depending on the type of signal. The correct answer therefore is choice (D).

The parasympathetic nervous system governs the “rest-and-digest” response. The parasympathetic nervous system slows the heart rate, decreases blood pressure, promotes blood flow to the GI tract, and constricts the pupils, among other functions. The sympathetic nervous system governs the fight-or-flight response, including increased heart rate and blood pressure, decreased blood flow to the digestive tract, and increased blood flow the muscles. Choice (D) is the only answer choice that represents a function of the parasympathetic nervous system.

Acetylcholine is the neurotransmitter released by the preganglionic neuron in both the sympathetic and parasympathetic nervous systems. The postganglionic neuron in the sympathetic nervous system usually releases norepinephrine, while the postganglionic neuron in the parasympathetic nervous system releases acetylcholine.

Neurons contain very specialized structures, including dendrites, axons, and the axon hillock. However, neurons are still cells and must carry out cellular functions including protein synthesis. The cell body or soma contains the nucleus, endoplasmic reticulum, and ribosomes.

First, consider the function of voltage-gated calcium channels. When the nerve terminal depolarizes, voltage-gated calcium channels open, allowing for influx of calcium. This influx of calcium triggers fusion of the synaptic vesicles containing neurotransmitters with the membrane of the neuron at the nerve terminal. This allows for exocytosis of the neurotransmitters into the synapse. If a disease blocked the influx of calcium, there would be no release of neurotransmitters. A lack of neurotransmitters means that the neuron cannot send signals. Thus, any symptoms resulting from this disease would be due to an inability of neurons to communicate. If neurons cannot communicate, flaccid paralysis may be one of the results.

Some neurons require multiple instances of excitatory transmission to be brought to threshold. These excitatory signals may be close to each other in time (temporal) or in space (spatial) either way, this pattern of excitation is termed summation.

Schwann cells are responsible for myelination of cells in the peripheral nervous system. Thus, the central nervous system is unlikely to be affected. The peripheral nervous system includes the somatic nervous system and the autonomic nervous system. The autonomic nervous system is composed of both the parasympathetic and sympathetic nervous systems. Thus, choice (A) is the right answer.

The dorsal root ganglion contains cell bodies of sensory neurons only. If a dorsal root ganglion is disrupted at a certain level, there will be a loss of sensation at that level.


  1. Do they force the cell to give up pumping out Na ions?
    No, the Na,K-ATPase (the sodium potassium pump) keeps active, also during the action potential (AP).
  2. Do the neurotransmitters themselves contain positively charged ions that the ion pumps are not sensitive to?
    They can, but neurotransmitter charge is irrelevant.
  3. Answer: Neurotransmitters bind to their corresponding receptors. An example excitatory neurotransmitter is glutamate (Glu). Glu has many receptors and one of them is the NMDA receptor. The NMDA receptor is coupled to a cation channel that opens when Glu binds (and other conditions pertain). In turn Na + and other depolarizing cations can enter the cell through the open channel. Other neurotransmitters and receptor mechanisms exist, but the coupling to a cation channel is a commonly encountered theme.
  1. Why are ions being pumped in and out of the axon in such a way to propagate an action potential?
    During an action potential, the voltage changes are not the result of ions being pumped in or out of the cell. Instead, ions flow along their concentration and charge gradients out or in the cell during an action potential. For example, Na + , a key ion in any action potential, flows passively into the cell during an action potential. Passive influx occurs, because Na + is continuously and actively pumped out of the cell into the extracellular fluid by the Na,K-ATPase. Moreover, the inside of the cell is highly negatively charged. Both the concentration gradient and charge gradient (i.e., the potential difference) will cause Na + to surge into the cell once Na + channels open. How then does it move across the axon? The trick is that Na + depolarizes the cell membrane. When for example Glu binds to its NMDA receptor, Na + enters the cell into the dendrite. Then, voltage-gated ion channels take over. Voltage-gated ion channels open or close depending on the local membrane potential. Most notably, voltage-gated sodium channels (VGSCs) open when the cell membrane depolarizes. Hence, after NMDA receptors are activated in the dendrite, Na + enters. This in turn depolarizes the dendrite and VGSCs open. This causes further depolarization and adjacent VGSCs open etc. etc. Voltage-gated potassium channels open after the VGSCs and re-polarize the membrane. An overview is provided in the following image from Antranik.org :

  1. Why isn't it just a positively charged signal running through the axon, without regard to the outside environment?
    Charges only move to an opposite charge. A neuron is not differentially charged from dendrite to axon terminal. Hence another way of action potential transduction is needed. Step-wise opening of VGSCs is a clever trick to use a constant cell membrane potential to generate a directional action potential.

To answer your question #5:

"Why are ions being pumped in and out of the axon in such a way to propagate an action potential?

As AliceD's answer provided, the ions during an action potential are not being pumped, and don't even need to be pumped, but just passively flow into or out of the axon due to the forces of electricity and diffusion. As an example, imagine a water balloon filled with dye, and you prick it with a pin underwater: the balloon need not pump the dye out, it will just diffuse out.

Why isn't it just a positively charged signal running through the axon,

There is a passive spread of charge down the length of the axon, at least for some short distance. However, axons are generally too long for that spread to get all the way to the end of the axon. Therefore, the signal must be amplified over and over down the length of the axon in order to (attempt to) insure it gets to the end.

without regard to the outside environment?"

Just a point of language here: When speaking of voltage (AKA potential), you need to refer to two positions, and when discussing the action potential we use the inside of the axon relative to the outside.


Endogenous firing patterns and ion channels in isolated vestibular somata

Most of our information about specific ion channels in vestibular afferents comes from experiments on isolated somata of the vestibular ganglion, which are relatively accessible and electrically compact for voltage clamp study. Dissociated vestibular somata have been studied with the whole-cell patch method by Desmadryl, Chabbert and colleagues(Autret et al., 2005 Chabbert et al., 1997 Chabbert et al., 2001a Chabbert et al., 2001b Desmadryl et al., 1997) and by Soto, Vega and colleagues (Limón et al., 2005 Mercado,2006). Whole-cell patch recordings have also been made from neurons cultured in semi-intact ganglia(Risner and Holt, 2006).

Our goal in reviewing the ion channel properties elucidated by these experiments on isolated somata is to consider insights they might provide into the firing regularity of afferent neurons as described with in vivorecordings. We begin by acknowledging several differences between the preparations that are likely to influence neuronal spiking. First, all studies on isolated somata have been conducted at room temperature rather than mammalian temperature, with probable but undocumented effects on the voltage ranges and kinetics of ion channels. Second, most afferent data are from adult animals, but most ion channel data are from rats and mice in the first two postnatal weeks, when dissociation and patching are easier. The early postnatal period is a time of active inner ear development for these animals. Hair cells are still being born up to about postnatal day 3 and afferent and efferent contacts are changing for much longer most calyces develop postnatally. Myelination occurs postnatally. Although much is known about vestibular hair cell development in these species (for reviews, see Eatock and Hurley, 2003 Goodyear et al., 2006), only Curthoys has examined maturation of their vestibular afferent activity(Curthoys, 1983). He found that rat semicircular canal afferents undergo developmental increases in background firing rates, average firing regularity and response gains over the first postnatal month. An increase in response gain is expected for the simple reason that the canal increases diameter during this period nevertheless, we also expect maturational changes in ion channel expression of vestibular afferents. With few exceptions, however, these have not been determined. Third, firing patterns arise when epsps interact with ion channels at the spike initiating zones of the peripheral dendrites of primary afferents(Fig. 2), and the overlap between ion channels in the somata and ion channels in the spike-initiating zones is largely unknown. Evidence suggests that some ion channels that are expressed in somata are also expressed in peripheral terminals [e.g. KCNQ4 channels and NaV1.5 channels(Hurley et al., 2006 Wooltorton et al., 2007)].

Vestibular ganglion somata produce either transient or sustained firing patterns in response to small depolarizing currents. (A,B) Voltage responses of two isolated somata to steps of +50 pA, recorded in whole-cell current clamp. Small depolarizing currents (4–200 pA) evoke single spikes(transient responses) in some neurons (A) and multiple spikes (sustained responses) in others (B). Somata dissociated from the mouse vestibular ganglion were recorded in the first postnatal week with a standard high-K + pipette solution and a bath of L-15 medium. Similar results have been obtained with perforated patch recordings and from rat vestibular ganglion somata (J.X., R.K. and R.A.E., unpublished observations). Arrows point to AHPs after the first spike and the offset of the step AHPs have longer repolarizing phases in the neuron with the sustained response (B).(C,D) Whole-cell current responses to voltage steps, recorded in voltage clamp from the same neurons as in A,B. Depolarizing steps (bottom panel) evoked large brief Na + currents followed by large steady outward K + currents. The sustained neuron (D) had prominent A and h currents, but it is not established that these differences influence the spike pattern.

Vestibular ganglion somata produce either transient or sustained firing patterns in response to small depolarizing currents. (A,B) Voltage responses of two isolated somata to steps of +50 pA, recorded in whole-cell current clamp. Small depolarizing currents (4–200 pA) evoke single spikes(transient responses) in some neurons (A) and multiple spikes (sustained responses) in others (B). Somata dissociated from the mouse vestibular ganglion were recorded in the first postnatal week with a standard high-K + pipette solution and a bath of L-15 medium. Similar results have been obtained with perforated patch recordings and from rat vestibular ganglion somata (J.X., R.K. and R.A.E., unpublished observations). Arrows point to AHPs after the first spike and the offset of the step AHPs have longer repolarizing phases in the neuron with the sustained response (B).(C,D) Whole-cell current responses to voltage steps, recorded in voltage clamp from the same neurons as in A,B. Depolarizing steps (bottom panel) evoked large brief Na + currents followed by large steady outward K + currents. The sustained neuron (D) had prominent A and h currents, but it is not established that these differences influence the spike pattern.

Despite these caveats, it is reasonable to inspect the available data on vestibular ganglion somata for evidence of distinct classes of neurons that may correspond to regular and irregular afferents.

Firing patterns evoked by depolarizing current steps

In keeping with the view that afferent spiking is driven by synaptic activity, isolated vestibular somata do not usually fire spontaneously. They do spike in response to depolarizing currents(Limón et al., 2005 Risner and Holt, 2006), as we illustrate for isolated mouse vestibular ganglion neurons in Fig. 3. Small depolarizing current steps evoke one of two basic classes of firing pattern: transient,comprising a single spike at the step onset(Fig. 3A), or sustained,comprising multiple spikes (Fig. 3B). (Sometimes a single spike is followed by large voltage oscillations, or ringing this may be a third category or an immature form of the sustained response.) The sustained and transient categories appear to correspond to the `low-threshold' and `high-threshold' categories,respectively, of Risner and Holt (Risner and Holt, 2006), who defined threshold as the minimum depolarizing current that could elicit one or more spikes. We choose the terms transient and sustained because this classification can be made on the spot, without reference to population distributions, and because it describes in vitro firing patterns that may be related to in vivo firing patterns. Specifically, we speculate that the regularity of sustained firing patterns reflects mechanisms that produce regular spike timing in vivo and the single spike of the transient response reflects mechanisms that support irregular spike timing in vivo. Support for this hypothesis comes from the spike waveforms of sustained and transient neurons:like regular vestibular afferents, neurons with sustained firing have AHPs that recover with a long steady trajectory that leads to a spike(Fig. 3B, filled arrows). In contrast, the AHPs of transient neurons are brief and lead to steady depolarization (Fig. 3A, filled arrows). This difference between the two neuron classes is particularly evident at the offset of depolarizing current steps(Fig. 3A,B), with the sustained response taking much longer to return to resting potential than the transient response. Thus, we suggest a simple equivalence between categories based on in vivo firing regularity (Table 1) and categories based on in vitro step-evoked firing patterns (Table 2).

Categories of vestibular ganglion somata in rodents

. . . . Channels . . . . . . .
Step-evoked firing pattern . Spike shape . Spike threshold (current) . Size . K (Ca) . Kv . KCNQ . Ca . Na . HCN . ASIC .
Transient Prominent AHP Higher Larger Lower total density proportionally more BK A KCNQ4 HVA LVA (T) TTX-sensitive TTX-insensitive (Nav 1.5?) Yes More
Sustained Brief AHP Lower Smaller More dense, more blocker-resistant current A ? HVA TTX-sensitive TTX-insensitive? (Nav 1.8, 1.9?) Yes Less
. . . . Channels . . . . . . .
Step-evoked firing pattern . Spike shape . Spike threshold (current) . Size . K (Ca) . Kv . KCNQ . Ca . Na . HCN . ASIC .
Transient Prominent AHP Higher Larger Lower total density proportionally more BK A KCNQ4 HVA LVA (T) TTX-sensitive TTX-insensitive (Nav 1.5?) Yes More
Sustained Brief AHP Lower Smaller More dense, more blocker-resistant current A ? HVA TTX-sensitive TTX-insensitive? (Nav 1.8, 1.9?) Yes Less

Current thresholds for evoking spikes are frequency-dependent(Risner and Holt, 2006). Differential expression of A and HCN channels may occur, but is unknown. We suggest that KCNQ4 and Nav 1.5 are present in large single-spiking neurons based on their reported expression in calyx terminals (see text). Nav 1.8 and Nav 1.9 transcripts are present in the ganglion we suggest they are expressed by small neurons by analogy with small DRG neurons (see text). The different channels are explained in the text and List of abbreviations. AHP, afterhyperpolarizing potential

An alternative or additional possibility is that the different firing patterns reflect different stages of maturation. Burst-type firing in immature cochlear afferents is assumed to help drive maturation of the entire auditory system [see discussion in Jones et al.(Jones et al., 2007)]. Multiple factors exogenous to the afferents have been implicated in their burst-type activity, including specific complements of ion channels that promote spiking by immature hair cells(Marcotti et al., 2003a Marcotti et al., 2003b),efferent actions on hair cells (Goutman et al., 2005) and periodic ATP release from supporting cells(Tritsch et al., 2007), but it is also plausible that the immature afferents' own ion channels contribute to spike bursts. Similarly, the low-threshold, sustained vestibular neurons might be in an immature state in which endogenous ion channels contribute to spontaneous bursts of spikes.

Parallels with other sensory neurons

Higher-order vestibular and auditory neurons

Type A second-order neurons of the medial vestibular nucleus receive input from regular primary afferents, have regular firing and prominent AHPs and generate sustained firing in response to small depolarizing current steps (for a review, see Straka et al.,2005). Type B second-order neurons receive both regular and irregular inputs, have irregular activity and small AHPs and generate mixed responses to small depolarizing steps (sustained with a transient component,also called phasic-tonic). In compartment models of the two neuronal types,differences in the kinetics of K channels and Ca 2+ influx were critical for reproducing differences in both resting discharge and frequency dependence (Av-Ron and Vidal,1999) (for a review, see Straka et al., 2005). Whether such mechanisms operate in primary afferents or not, the diversity of firing regularity in both primary and higher order vestibular neurons reinforces the notion that the diversity has a sensory function.

The bushy and stellate cells of the ventral cochlear nucleus also provide interesting parallels (for reviews, see White et al., 1994 Eatock, 2003). Bushy cells generate transient responses to current steps. Like irregular vestibular afferents, bushy cells have irregular inter-spike intervals and generate brief epsps that closely follow the primary afferent input. In another parallel, the bushy cell pathway is characterized by large synaptic endings: the bushy cells receive primary afferent input at large synaptic endbulbs on their somata and in turn make very large calyceal synaptic terminals (calyces of Held) on higher-order neurons. Also, bushy cells, like type I hair cells(Correia and Lang, 1990), have K + conductances at rest that shorten the membrane time constant(Manis and Marks, 1991). These specializations all appear to be designed to speed signals along this auditory timing pathway indeed, bushy cells can phase-lock to much higher sound frequencies than can stellate cells. Stellate cells produce sustained, regular firing in response to current steps. In response to sounds, they show temporal and spatial summation of epsps produced at many small dendritic synapses far from the somata. They are called `choppers' because their tone burst responses show preferred (regular) inter-spike intervals that are unrelated to either the sound frequency or the best frequency of the auditory tuning curve.

Other sensory ganglia

Inspection of spike patterns evoked by current steps in auditory (spiral)ganglion somata (Reid et al.,2004) shows that some neurons produce single spikes while others produce multiple spikes. Dissociated somata from the dorsal root ganglion(DRG) may also show sustained firing (Rush et al., 2007). As we are suggesting for the vestibular ganglion,sustained firing patterns in the spiral ganglion and DRG are associated with small neuronal size.

Work over many decades has sub-divided sensory ganglia into discrete neuronal populations based on such properties as somatic and axonal diameters,terminal morphology and targets, expression of structural proteins such as neurofilaments and Ca 2+ binding proteins. There are certain parallels between the differences distinguishing small and large neurons in vestibular, auditory and dorsal root ganglia. Small neurons express peripherin, a type III intermediate filament protein(Oblinger et al., 1989 Després et al., 1994 Hafidi, 1998 Lysakowski et al., 1999)large neurons do not. Targets or terminals differ between small and large neurons. In the vestibular ganglion, large somata give rise to large calyceal and dimorphic afferents that innervate the striolar and central zones, while small somata give rise to thin bouton and dimorph afferents that innervate the extrastriolar and peripheral zones (Table 1). In the DRG, large somata give rise to fast-conducting mechanosensory afferents while small somata give rise to unmyelinated C-fibers of multiple sensory modalities (Lawson,2002). In the spiral ganglion, large somata give rise to relatively large type I fibers that contact inner hair cells and carry afferent signals to the brain, while small somata give rise to thin type II fibers that contact outer hair cells but have unknown function – their sound-evoked responses have never been documented (see Reid et al., 2004).

There are also differences across ganglia in such significant features as myelination and firing rate. In the dorsal root and spiral ganglia, the smallest neurons and their fibers are unmyelinated. In contrast, myelination is a general feature of vestibular afferent fibers and somata of all diameters, although the wrapping of somata is looser and thinner than the compact myelin around fibers (Toesca,1996). Small DRG afferents have low spontaneous spike rates [<5 spikes s –1 (Djouhri et al., 2006)]. In contrast, small vestibular afferents can have very high background rates (>50 spikes s –1 ). Confirmed recordings from very small vestibular afferents are rare, as these have the smallest diameters and therefore resist intracellular recording and labeling. In three large intra-axonal labeling studies, there are just two labeled bouton afferents (Baird et al.,1988 Goldberg et al.,1990b Schessel et al.,1991) both had very regular discharge and high background firing rates. The difference in background spike rates between DRG and vestibular ganglion neurons may reflect differences in the sensory functions of the two types of neuron. Regular vestibular afferents are bombarded by neurotransmitter released by many hair cells, providing a high, sustained level of firing that can be modulated up and down, allowing them to signal hair bundle motions in two directions. Spike activity in small DRG neurons is driven by modulation of noci- or chemo-sensitive ion channels in peripheral nerve endings background levels of activation are evidently unnecessary for sensory function.

Ion channel classes expressed in vestibular ganglion somata

The differences in current-clamped voltage responses and voltage-clamped current responses illustrated in Fig. 3 indicate that vestibular somata express different complements of voltage-gated ion channels. In the following paragraphs we review what is known about ion channel classes in vestibular afferent somata, including Ca 2+ -dependent K + conductances, voltage-dependent K + , Na + , Ca 2+ conductances,hyperpolarization-activated cyclic-nucleotide-modulated (HCN) conductances and acid-sensing (ASIC) conductances (Table 2). In general, it is not yet clear how these conductances relate to the current clamp responses, apart from the conservative assumptions that Na + currents contribute to the upstroke of action potentials,K + currents contribute to the repolarizing and afterhyperpolarizing phases and Ca 2+ currents will activate Ca 2+ -dependent K channels and, if also present at the neuronal terminals in the brain, drive the exocytosis of transmitter.

Because AHPs distinguish both the action potentials of regular and irregular afferents and the action potentials of sustained and transient responses of isolated somata, we are particularly interested in conductances that may contribute to AHPs. In general, AHPs are most prominent in pacemaking neurons and neurons that, like the sustained vestibular neurons, fire trains of spikes in response to current steps. AHP conductances contribute to the relative refractory period by hyperpolarizing the neuron and/or by increasing its conductance, reducing the depolarizing effect of inward currents such as excitatory postsynaptic currents (epscs) or persistent Na + currents. In this way, AHP conductances help set firing rate, firing regularity and precision of spike timing. They have been extensively analyzed in principal neurons of rodent hippocampus and neocortex (e.g. Bond et al., 2005 Storm, 1990), where they have at least three kinetic phases (Bean,2007 Disterhoft and Oh,2007 Storm, 1989 Vervaeke et al., 2006). A slow, poorly understood phase lasts for seconds. A medium phase, 50–200 ms after a spike burst, involves HCN channels, Ca 2+ -dependent K channels (K(Ca) channels) of the SK class and M channels. The fast phase, the downstroke of the spike, involves one or more rapid K channels, especially the BK variety of K(Ca) channels, M channels and A channels. As described below,there is evidence for expression of BK, SK, M, A and HCN classes in vestibular ganglion neurons.

K channels

Depolarizing voltage steps evoke large outward currents in vestibular ganglion somata (Fig. 3C,D). Chabbert and colleagues (Chabbert et al.,2001a) used K channel blockers to identify three K + currents in mouse vestibular ganglion somata of the first postnatal week. Because Ca 2+ entry was blocked in these experiments, all three currents were assumed to be Ca 2+ -independent. One current was a rapidly inactivating A current, blocked by 4-aminopyridine (4-AP) and dendrotoxin. An A current was also identified in a semi-intact preparation of the mouse vestibular ganglion (Risner and Holt, 2006).

Limón and colleagues(Limón et al., 2005)studied the K(Ca) currents of rat vestibular ganglion somata in the second postnatal week. They pharmacologically identified BK, IK and SK (Big-,Intermediate- and Small-K) conductances plus a fourth component resistant to known K(Ca) channel blockers. The proportions of each K + current type within a given neuron varied with the Ca 2+ conductances expressed and with soma size. As shown previously for mouse vestibular ganglion somata (Desmadryl et al.,1997 Chambard et al.,1999), all rat vestibular ganglion somata were found to have high-voltage-activated (HVA) Ca 2+ conductances medium-large somata have low-voltage-activated (LVA, or T-type) Ca channels as well. Small neurons have the highest total densities of K(Ca) current and proportionally more blocker-resistant current, while large neurons have higher proportions of BK current.

Given the strong correlation between axonal diameter and irregularity of spike timing (Table 1), large somata with T channels and proportionally more BK channels are likely to belong to afferents that are irregular in vivo. If so, then they are also likely to express high levels of calbindin-D28K, as shown for large-diameter calyx-bearing afferents(Bäurle et al., 1998 Kevetter and Leonard, 2002 Leonard and Kevetter, 2002)(Table 1). Many also express calretinin. Although early studies found no differences in calretinin and calbindin localization (Desmadryl and Dechesne, 1992 Raymond et al., 1993), more recent results suggest that calretinin antibody specifically labels pure-calyx afferents(Desai et al., 2005a Desai et al., 2005b Leonard and Kevetter, 2002)while calbindin-D28K antibody may label central and striolar dimorphic afferents in addition to pure-calyx afferents(Leonard and Kevetter, 2002)(Fig. 2). Thus, antisera to Ca 2+ binding proteins are used as markers of epithelial zones, but there has been no attempt to understand the significance of the association between Ca 2+ binding proteins and afferent classes. One possibility is that specific Ca 2+ binding proteins, Ca channels (below) and K(Ca) channels together form a system that regulates firing patterns by regulating the activation of K(Ca) channels. The effective range, spatially and temporally, of Ca 2+ entering through Ca channels is determined by the mobility and affinity of Ca 2+ binding proteins and the relative affinity of K(Ca) channels. For example, in frog saccular hair cells,the speed of the mobile endogenous buffer and the low affinity of the BK channels guarantee that Ca 2+ entering voltage-gated Ca channels interacts only with BK channels that are physically very near the channels(Roberts et al., 1990).

Given the involvement of K(Ca) channels in AHPs and firing patterns in brain neurons (above), it is natural to suggest that they play a role in setting firing patterns in the vestibular ganglion neurons. In hippocampal pyramidal cells, BK current is important for both high-frequency firing(>40 spikess –1 ) and spike adaptation(Gu et al., 2007). It is interesting that blocking BK channels would reduce high-frequency firing one might have expected blocking K channels to enhance excitability. The effect apparently occurs because the block lengthens the spike – implicating BK channels in the downstroke – and the increased spike duration permits the activation of slower K channels, which increases the refractory period. Similarly, type I auditory afferent neurons in BK-null mice have abnormally low spike rates and diminished precision of spike timing(Oliver et al., 2006). In vestibular ganglion somata, blocking BK current broadens spikes and slows spike rate adaptation evoked by current steps(Limón et al., 2005). A caveat is that these experiments were conducted in 10 mmoll –1 4-AP to block non-Ca 2+ dependent K + currents, such as the A current the influence of BK conductances may differ in the context of the full set of conductances.

Neuronal M currents, which activate at relatively negative potentials and do not inactivate, can play important roles in setting resting potentials and sub-threshold conductance levels. It is generally agreed that some M currents are carried by members of the KCNQ (Kv7.x) family of K channels there may also be contributions from the erg subfamily of the ether-a-go-go K channel family (Kv11.x) (Hurley et al.,2006 Selyanko et al.,2002). RT-PCR experiments on isolated vestibular ganglia revealed expression of all three erg subunits and all KCNQ subunits tested [KCNQ3,KCNQ4 and KCNQ5 (Hurley et al.,2006)]. Although the presence of M-like current in vestibular ganglion somata has not been established, it may contribute to the voltage-sensitive, non-A-type, K + conductances described(Chabbert et al., 2001a Risner and Holt, 2006). In addition, there is evidence for M-like currents in calyx terminals:application of a KCNQ blocker to an isolated calyx ending revealed a KCNQ-like current (Hurley et al., 2006)and KCNQ4-like immunoreactivity is intense in the postsynaptic membranes of calyces, especially in central and striolar zones where spiking is irregular(Hurley et al., 2006 Kharkovets et al., 2000). In other neurons, blocking M current can change a short burst of spikes during a small current step to a prolonged train(Hernández-Ochoa et al.,2007). Thus, M currents in calyces might inhibit repeated firing and so contribute to the transient firing pattern that we associate with large, calyx-bearing irregular afferents.

Ca channels

Because they are activated by small depolarizations from resting potential,the low-voltage-activated T-type Ca channels can exert an important effect on excitability. T channels are widespread in embryonic mouse vestibular afferent neurons, but disappear from 80% of neurons by the middle of the first postnatal week (Chambard et al.,1999). In the remaining 20% of neurons, the T current density increases over the same period these are presumably the large neurons described by Limón et al. as having both HVA and LVA (T-type)Ca 2+ currents (Limón et al., 2005). It is not clear how T currents might contribute to a single-spiking phenotype in such neurons. In late-embryonic mice, T channels with the biophysical characteristics of CaV3.2 subunits contribute a post-spike depolarization [after-depolarizing potential, ADP(Autret et al., 2005)]. Similar ADPs may contribute to burst firing in `D hair' DRG neurons, which are medium-sized, slowly adapting mechanosensory neurons blocking CaV3.2 currents eliminates their slow ADP and increases the threshold amount of current required to evoke a spike(Dubreuil et al., 2004).

Desmadryl et al. (Desmadryl et al.,1997) pharmacologically dissected the high-voltage-activated Ca 2+ currents into L-, P-, Q-, N- and R-type currents. With RT-PCR screens of the rat vestibular ganglion(Tsai et al., 2005), we detected pore-forming α subunits corresponding to each of these current types: CaV1.3 and CaV1.2 (L-type), CaV2.1(P/Q-type), CaV2.2 (N-type) and CaV2.3 (R-type), as well as all three T-type subunits (CaV3.1, 3.2 and 3.3). L-, N-, P- and Q-type currents are present at roughly similar densities (10–25 pApF –1 ) in mouse vestibular ganglion somata in the first postnatal week (Chambard et al.,1999). Changes in density of the N, P and Q currents occur between embryonic day 15 and postnatal day 4.

The reasons for the multiplicity of high-voltage-activated Ca channels in vestibular ganglion somata are not known. While some Ca channels may couple to K(Ca) channels, vestibular ganglion somata may also express Ca channels that have their main impact at terminals, either contributing to transmitter release at central terminals on brainstem or cerebellar targets, or responding to hair cell or efferent inputs in the periphery(Fig. 2).

Na channels

As needed for high spike rates, vestibular afferents have large voltage-gated, fast-inactivating Na + currents. These have been recorded at room temperature from mouse and rat vestibular ganglion somata in the first postnatal week (Chabbert et al.,1997 Schneider et al.,2006) and from isolated calyx terminals(Hurley et al., 2006 Rennie et al., 2005 Rennie and Streeter, 2006). They have fast activation and inactivation kinetics and relatively negative voltage dependence, with an activation midpoint of –40 mV and an inactivation midpoint of –70 mV(Chabbert et al., 1997) or–80 mV (Hurley et al.,2006 Rennie and Streeter,2006).

Chabbert et al. (Chabbert et al.,1997) treated the current as homogeneous and reported it to be sensitive to low levels of the classic Na channel blocker, tetrodotoxin (TTX). Our preliminary results on rat vestibular ganglion somata suggest that some vestibular somata also express a Na + current that is less sensitive to TTX and has a more negative inactivation range(Schneider et al., 2006). The combination of negative voltage dependence, fast kinetics and TTX insensitivity suggests the cardiac Na channel subunit, NaV1.5. RT-PCR screens of vestibular ganglia revealed expression of most Na channel subunits, including NaV1.5(Schneider et al., 2006). NaV1.5-like-immunoreactivity is intense on the inner face of the calyx terminal, particularly in the striolar zone(Wooltorton et al., 2007). The negative inactivation range raises questions about the physiological function of such channels, as they appear to spend most of their time inactivated in the physiological voltage range [for a discussion of similar channels in vestibular hair cells, see Wooltorton et al.(Wooltorton et al., 2008)]. It is possible that the inactivation range is less negative at mammalian temperatures (Oliver et al.,1997).

In screening for TTX-insensitive channels, we discovered that the vestibular ganglion also expressed both NaV1.8 and NaV1.9 subunits (Wooltorton et al., 2007), which are considerably more TTX-resistant than NaV1.5 subunits and have much slower kinetics. We have no direct information about the function of such channels in vestibular ganglion neurons, nor even their localization, but hints may be derived from studies of DRG neurons, where the subunits were first described. All three TTX-insensitive channels occur in rat small DRG neurons, though not at the same time (Renganathan et al.,2002): over the period of a week centered on birth, the incidence of NaV1.5 falls from 80% to ∼10% and the incidence and density of NaV1.8 and NaV1.9 currents increase dramatically. Thus, in DRG neurons, NaV1.5 appears to be an immature current whose disappearance coincides with the appearance of NaV1.8 and NaV1.9. In small DRG neurons, null mutant studies show that NaV1.8 channels support multiple spiking during sustained depolarization (Rush et al.,2007). This effect is attributed to the channels' relatively depolarized inactivation range and rapid recovery from inactivation, which may produce a persistent inward current to counter-balance the post-spike inactivation of transient Na + currents. NaV1.9 channels also have very slow activation and inactivation kinetics but a more hyperpolarized activation range too slow to contribute to the action potential upstroke, they reduce spike threshold by providing persistent depolarizing currents (Rush et al.,2007). By analogy with these observations on small DRG neurons, we wonder if the NaV1.8 and NaV1.9 subunits contribute to multiple spiking and regular firing in small vestibular neurons.

HCN channels

Like many neurons, including DRG neurons(Doan et al., 2004), mouse vestibular ganglion somata have Ih, the hyperpolarization-activated mixed-cation current carried by HCN channels(Chabbert et al., 2001b), as illustrated in Fig. 3C,D. Ih is held to be involved in pacemaking – the endogenous generation of regular spikes – in cardiac cells and other neurons,although how it plays this role is not understood (reviewed in Siu et al., 2006). In some settings, Ih may inhibit repeated firing, as shown by blocking it in large DRG neurons (Doan et al.,2004). But blocking Ih in immature mouse vestibular ganglion somata had no effect on either the spike waveform, including the AHP,or the resting potential (Chabbert et al.,2001b). This lack of influence is easily understood from the very negative activation range (negative to –80mV) reported in these neurons. It is possible that through developmental maturation of the neurons or under more physiological conditions, such as mammalian body temperature, the activation range is shifted such that the channels have more influence.

ASIC channels

Acid-sensing conductances of the DEG/ENaC family are particularly large in small vestibular ganglion somata, where they contribute to spiking evoked by superfusion with acidic solutions(Mercado, 2006). ASIC channels are also found in spiral ganglion neurons(Peng et al., 2004) and DRG neurons (Benson et al., 2002). Their prominence in eighth-nerve ganglion somata provides another parallel with DRG neurons. In the latter they seem well positioned to serve nociception, but attempts to establish a sensory function for them have produced mixed results (Wemmie et al.,2006). ASIC2 channels are present in both spiral and vestibular ganglion neurons and ASIC2 null mutants show reduced temporary noise damage,suggesting that proton-activated ASIC2 channels may contribute to noise-induced excitotoxic damage to spiral ganglion neurons(Peng et al., 2004).

In summary, large neuronal somata, presumed to be irregularly firing in vivo, have different combinations of Ca and K(Ca) channels and fewer ASIC channels than do small somata, which are presumed to be regularly firing in vivo. M, Na and HCN channels may also be differentially expressed by irregular and regular afferents it is also likely that some of the variability in their expression reflects changes with development in early postnatal tissue. These channels all have the potential to contribute to the step-evoked firing patterns and AHPs of isolated somata and to help set afferent firing regularity in vivo.


Nodes of Ranvier

Nodes of Ranvier are microscopic gaps found within myelinated axons. Their function is to speed up propagation of action potentials along the axon via saltatory conduction [1] .

The Nodes of Ranvier are the gaps between the myelin insulation of Schwann cells which insulate the axon of neuron.

The Node of Ranvier is the 1-2 micrometre gap between the glial cells of the myelin sheath. These glial cells are called Schwann cells, and they help to electrically insulate the neuron. The Nodes of Ranvier are only present when the axon of a neuron is myelinated. Myelination allows for an increased rate of action potential transmission due to action potentials "jumping" between Node of Ranvier, this is called saltatory conduction.

The movement of sodium ions to depolarize the membrane can only occur at the Node of Ranvier, as the sodium voltage-gated channels are found only at the nodes of Ranvier [2] . The Schwann cells of the myelin sheath block the movement of sodium ions elsewhere along the axon.

However, in multiple sclerosis (MS) the myelin sheath is degraded which leads to demyelination. This allows for action potentials to move as current loops instead of by saltatory conduction, which slows the transmission of action potentials and therefore a decrease in reaction time.

The interruptions in the myelin sheath were first discovered in 1878 by a French histologist and pathologist called Louis-Antoine Ranvier, who first described the nodes as constrictions [3] .

The Nodes of Ranvier are pivotal in the process of saltatory conduction. The Nodes themselves are approximately one micrometre in length apart, and they are the physical gaps between the myelin sheath cells themselves [4] . The action potential can jump from node to node along the axon, causing the transmission speed to increase and reach around 120 metres per secondl. The myelination sheath produced by the Schwann Cells increases the membrane resistance (Rm), which, along with an increased diameter (D) of the axon, will increase the velocity of the action potential. This is outlined by using the equation:

The gaps are rich in ion channels, such as sodium and calcium ion channels, resulting in maximised speed at which ion mediators can be released into tissues and adjacent neurones. This is particularly handy at the synaptic cleft (the area between a pre and a postsynaptic neurone), because the quicker that sodium ions are released into the cell, the quicker that depolarisation can occur and the faster a response is produced as a result of the action potential that is caused [6] .

Overall, myelination is a highly specialised property of axons and ensures that impulses travel at sufficiently high speed around the autonomic nervous system so that the body can produce a successful response.


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