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Neuronal Excitation

Neuronal Excitation - Equilibrium & Membrane Potential, Action Potentials, and Neuronal Signalling

Equilibrium Potentials

Electrochemical Gradient of Sodium

There is a far greater concentration of sodium ions outside of the cell than inside; a ratio of roughly 15:1.
Although no one knows for sure about the origins of cells, it's helpful to imagine cellular life originating from seawater, growing up in salty extracellular environment.

For reference, seawater has a salinity of 3.5% (35 grams per liter).

For sodium, the intracellular concentration is ~ 10 mEq/L and the extracellular concentration is 140 mEq/L.
Each of the positive sodium charges is balanced with negative chloride ions.

The primary negative charges within neurons are chloride ions and organic anions.

Channels: a sodium leak channel allows sodium ions to flow freely down their chemical gradient – from a region of high ion concentration, outside of the cell, to low ion concentration, inside of the cell.
Cell membranes are lipid bilayers, which are impervious to charged molecules (polar molecules), such as electrolytes (only nonpolar molecules (eg, oxygen) freely pass across the lipid bilayer). For this reason, electrolytes (which becomes ions when dissolved in water) require channels in order to cross the membrane.
Were it not for a separation in charge, sodium ions would fill the cell until there were even intracellular and extracellular concentrations.
But chloride ions cannot pass through the channel, which creates a separation in charge.
So, a positive charge forms within the cell.
This positive charge generates an electrostatic force directed in opposition to the chemical gradient (remember: like-charges repel one another).

Electrochemical equilibrium

At electrochemical equilibrium, the chemical and electrical gradients are balanced.

Equilibrium potential

The equilibrium potential, V(eq), (aka reversal potential) is the membrane potential at which an ion reaches electrochemical equilibrium.
We can predict the equilibrium potential by using the Nernst equation.

Membrane potential

Membrane potential, V(m), is the voltage potential of the intracellular space in reference to the extracellular space.
With the use of a voltmeter, we can determine the membrane potential: it is simply the difference between the intracellular and extracellular spaces.
We can predict the membrane potential by using the Goldman-Hodgkin-Katz equation.

Equilibrium potential of Sodium

The equilibrium potential for sodium is + 60 mV.

Summation

Tying these three key concepts together, if a cell is only permeant to a single ion, then at electrochemical equilibrium, the membrane potential is equal to the equilibrium potential of that ion.
But cell membranes are permeant to many different ions, so the membrane potential actually relies on the equilibrium potential for many different ions, and these potentials are a part of the Goldman-Hodgkin-Katz equation.
Even still, potassium is far and away the most permeant ion in a neuronal membrane, so although we have to account for multiple ions to determine the membrane potential, the strongest influencer is potassium.
As we can see in the Goldman-Hodgkin-Katz equation, an ion's ability to permeate the membrane is a key factor in its mathematical influence on the equation. Put another way, an ion's equilibrium potential is irrelevant to the overall membrane potential, if there are too few channels for that ion to generate very much of an electrochemical gradient.
Thus, as it turns out, the Nernst equation calculation for the equilibrium potential of potassium is actually very near to the Goldman-Hodgkin-Katz calculation for the membrane potential of a neuron.

Potassium

Electrochemical Gradient of Potassium

There is a much greater concentration of potassium ions inside of the cell than outside; a ratio of ~ 35:1.
For neurons, potassium has an intracellular concentration of ~ 140 mEq/L and an extracellular concentration of ~ 4 mEq/L.
Again, balance those charges with chloride ions.

Equilibrium Potential of Potassium

When a potassium channel opens, there is an efflux of ions out of the neuron, which creates a negative charge within the cell.
The membrane potential of potassium is - 90 mV, which, as we'll see, is similar to the neuronal membrane potential.

Neuronal Membrane Potential

Three major electrolytes (sodium, potassium, and chloride) populate the intracellular and extracellular spaces of the neuron.

Sodium

Sodium has a high extracellular concentration and a low intracellular concentration.
Sodium enters the cell via leak channels down its concentration gradient and include the opposing electrostatic gradient.

Potassium

Potassium has a low extracellular concentration and a high intracellular concentration.
At rest, potassium exits the cell via leak channels along its concentration gradient and include an opposing electrostatic gradient.
Potassium leak channels dominate the permeance of the resting neuronal cell membrane.
The resting membrane potential of a neuron is around - 70 mV. Again, very near to that of potassium.
Again, because potassium is the most permeant ion in a neuron, the neuron membrane potential essentially takes on the equilibrium potential of potassium.

Sodium-potassium ATPase pump

The sodium-potassium ATPase pump resets the ion concentrations. It maintains the resting membrane ionic concentrations and resultant membrane potential.
It redistributes 3 sodium ions out of the cell for every 2 potassium ions it pulls back into the cell. The sodium-potassium ATPase pump requires energy, in the form of ATP, because it is an active transporter: it performs an energy-requiring process.

Chloride

Chloride has a high extracellular concentration and a low intracellular concentration; a ratio of ~ 11:1.
It has a concentration gradient directed into the cell body and an opposing electrostatic gradient.
Chloride has an intracellular concentration of ~ 10 mEq/L and an extracellular concentration of ~ 110 mEq/L.
Chloride has an equilibrium potential of - 80 mV, which is fairly close to the membrane potential, itself, which brings us to the concept of driving force.

Electrochemical driving force

The electrochemical driving force, V(DF), is a measure of the electromotive force on an ion. To calculate driving force, we subtract the equilibrium potential from the membrane potential. The greater the difference between the two potentials, the greater the driving force.
Chloride has a low driving force because the equilibrium potential for chloride is near to the neuronal membrane potential.
For some cells, chloride concentrations will be able to adjust themselves so the equilibrium potential will evenly match the membrane potential, and there will be no net driving force, whatsoever.

Neuronal Signaling

Synapse

A presynaptic cell foot process (the axon terminal).
The postsynaptic cell dendrite (the target).
The synaptic cleft between the two.
Neurotransmitters are chemicals that provide communication between the pre- and postsynaptic cells.

Calcium channels

Voltage-gated calcium ion channel.
Action potentials travel down the presynaptic cell axon and depolarize the axon terminal (through sodium influx via voltage-gated sodium channels), which ultimately triggers voltage-gated calcium ion channels to open.

There are numerous calcium channel subtypes but its helpful to know that the N- and P/Q subtypes are the best described presynaptic high-voltage-gated calcium channels.

Calcium has an extracellular to intracellular concentration ratio of > 10,000:1, thus, so it has a very positive equilibrium potential: + 140 mV and a large driving force.
Calcium ions rush into the cell and initiates a signaling cascade wherein synaptic vesicles fuse with the presynaptic membrane and release neurotransmitter into the synaptic cleft.

Ligand-Gated Sodium Ion Channels

Ligand-gated (a neurotransmitter-activated) sodium ion channel.
Neurotransmitters diffuse across the synaptic cleft to a receptor on the ligand-gated ion channel, triggering it to open.

Glutamate is an important neurotransmitter that can bind to NMDA and AMPA receptors on these ligand-gated sodium ion channels to depolarize the postsynaptic membrane.

Sodium ions, then, enter the postsynaptic cell down their electrochemical gradient, which slightly depolarizes the postsynaptic membrane – makes it more positive.

Voltage-Gated Sodium Ion Channels

Voltage-gated sodium channels: when the depolarization reaches a certain voltage threshold, voltage-gated sodium ion channels open.
Sodium rushes into the cell, which causes further depolarization in a feed-forward cycle.
This positive feedback system of depolarization propagates the action potential down the postsynaptic membrane and in this manner neuronal signaling passes from one neuron to the next.

Action Potentials

Overview

Depolarization signals that operate over long distances (along an axon); they are all-or-nothing events – like firing a gun.

Key voltages: -70 mV (the resting potential), - 55 mV (the action potential threshold), 0 mV, and + 30 mV (the peak of the action potential).

Resting Membrane Potential

At time 0, the resting state membrane potential is at -70mV.
The voltage-gated-ion channels are closed and that potassium leak channels are the driving force. They drive the membrane potential towards the equilibrium potential of potassium.

Depolarization

Then, at time = 1 ms, via a graded depolarization, the membrane potential slowly becomes less negative (it depolarizes), due to opening of ligand-gated ion channels.
At -55mV, the depolarization, starts a steep climb, reflecting a rapid depolarization.
This value is the "threshold".
During depolarization, ligand-gated sodium channels open, followed by voltage-gated sodium channels, with rapid opening at threshold (-55 mv).
The membrane potential rapidly increases and peaks at about +30 mV, nearing towards the equilibrium potential for sodium.

The rapid opening of sodium channels elicits a rush of sodium influx, which is the primary driver of the spike in membrane potential.
This spike causes a massive depolarization, which distributes along the membrane in a self-generating, feed-forward process.

Voltage-gated potassium channels open more slowly sodium channels, requiring time to counter the positive sodium ion influx with an efflux of positive potassium ions.

Repolarization

At ~ 2 ms, the potential reverses and drops: there is increasing negativity of the membrane potential.
Repolarization reflects that at this time the sodium channels are becoming inactivated, which means that even if the membrane potential is above threshold, they cannot open: they are inactive. And the voltage-gated potassium channels are now opening.
Inactivation of sodium channels prevents action potentials from propagating in reverse.

Hyperpolarization

During this time period, there is hyperpolarization of the membrane potential, because the equilibrium potential of potassium of – 90 mV, so there is net ionic driving force on potassium to leave the cell all of the way down to this potential.
The sodium channels are closed and the voltage-gated potassium channels remain open beyond the point where the membrane potential reaches its resting state.
Finally, around 4 ms after beginning of depolarization (time = 5ms), the membrane potential returns to its resting state level; at this point the voltage-gated potassium channels are closed and only the leak channels are open.

Refractory Periods

Absolute Refractory Period

Begins when the voltage reaches threshold and ends during repolarization.

No stimulus, no matter how strong, can cause another action potential during this period because the channels are either already open (during the depolarization) or inactivated (during repolarization).

Relative Refractory Period

The time when the sodium channels are recovering from inactivation and the potassium channels remain open. It begins at the end of the absolute refractory period and it ends when the membrane potential returns to the resting potential.
It is possible for a stronger than normal stimulus to cause another action potential during this period but two forces oppose the possibility of depolarization: the slowly recovering sodium channels (which are coming out of inactivation) and the persistent opening of the voltage-gated potassium channels.

Additional Information

We discuss these topics in further detail in the following tutorials:

Neuronal Excitation

Related Tutorials