Nerve Cell Membrane Potentials

• Nerve cells use electrical signals to transmit information, relying on ion flow across their plasma membranes
• Neurons maintain a negative resting membrane potential, which action potentials transiently abolish by making the transmembrane potential positive
• Action potentials propagate along axons, serving as the primary means of transmitting information in the nervous system

Electrical Potentials across Nerve Cell Membranes

• Neurons use electrical signals to encode and transfer information
• Intracellular microelectrodes measure the electrical potential across the neuronal plasma membrane
• Microelectrodes are fine-pointed glass tubes filled with a conductive salt solution connected to a voltmeter

Resting Membrane Potential

• Upon insertion, microelectrodes reveal a negative potential, known as the resting membrane potential
• The resting membrane potential varies depending on the neuron type but typically ranges from -40 to -90 mV

Receptor Potentials

• Stimuli can change the resting membrane potential
• Receptor potentials occur when sensory neurons are activated by external stimuli (light, sound, or heat)
• Example: touching skin activates Pacinian corpuscles, creating a receptor potential that briefly alters the resting potential

Synaptic Potentials

• Synaptic potentials occur at synaptic contacts between neurons
• Synaptic potentials facilitate information transfer from one neuron to another
• Activating a synapse on a hippocampal pyramidal neuron causes a brief change in the resting membrane potential

Action Potentials

• Neurons have a "booster system" to conduct electrical signals over long distances due to the axons poor electrical conductivity
• Electrical signals produced by this "booster system" are action potentials, also called spikes or impulses
• Action potentials can be elicited by passing electrical current across the neuron's membrane

Hyperpolarization

• Injecting current that makes the membrane potential more negative causes hyperpolarization
• Hyperpolarizing responses are passive electrical responses

Depolarization

• Injecting current that makes the membrane potential more positive causes depolarization
• Depolarization leads to an action potential when the membrane potential reaches the threshold potential

Action Potential Properties

• An action potential is a brief (1 ms) shift from negative to positive in the transmembrane potential
• The amplitude of the action potential is independent of the current magnitude used to evoke it (all-or-none)
• Stimulus intensity is encoded by the frequency of action potentials, not their amplitude
• Receptor potentials have amplitudes proportional to the stimulus, while synaptic potential amplitudes vary with synapse activity

Ion Movement

• Neuronal electrical signals rely on ion movement across the neuronal membrane
• Nerve cells use ions to generate electrical potentials
• Chapter 3 explores action potential production and long-distance electrical conduction in nerve cells
• Chapter 4 examines membrane molecules responsible for electrical signaling
• Chapters 5–7 consider electrical signal transmission at synaptic contacts

Ionic Movements

• Electrical potentials are generated across cell membranes due to:
• Differences in concentrations of specific ions
• Membranes being selectively permeable to some of these ions
• Active transporters actively move ions against concentration gradients
• Ion channels allow certain ions to cross the membrane down their concentration gradients

Role of Transporters

• Active transporters establish ion concentration gradients

Role of Ion Channels

• Ion channels cause selective permeability, allowing ions to diffuse down their concentration gradients
• Channels and transporters work against each other to generate the resting membrane potential, action potentials, and synaptic/receptor potentials

Membrane Potential

• Consider a simple system where an artificial membrane separates two compartments containing solutions of ions
• Determine the composition of the two solutions and control ion gradients across the membrane
• For a membrane permeable only to K+ ions, equal K+ concentrations on both sides result in no electrical potential

Potassium Concentration

• If K+ concentration differs, an electrical potential is generated
• A tenfold higher K+ concentration on one side (compartment 1) makes its electrical potential negative relative to the other side (compartment 2)
• K+ ions flow down their concentration gradient, carrying positive charge
• Neuronal membranes contain pumps that accumulate K+ in the cell cytoplasm

Electrochemical Equilibrium

• K+ movement from compartment 1 to compartment 2 generates a potential that impedes further K+ flow
• The potential gradient repels positive potassium ions, counteracting their movement
• Net K+ movement stops at equilibrium when the potential change offsets the concentration gradient
• At electrochemical equilibrium, the concentration gradient is balanced by the opposing electrical gradient

Ion Balance

• The number of ions needed to flow to generate this electrical potential is very small (approximately 10–12 moles of K+ per cm2 of membrane, or 1012 K+ ions)
• The concentrations of permeant ions on each side of the membrane remain essentially constant
• Tiny ion fluxes do not disrupt chemical electroneutrality because each ion has an oppositely charged counter-ion

Nernst Equation

• Predicts the electrical potential generated across the membrane at electrochemical equilibrium (the equilibrium potential)
• Expressed as: EX = (RT/zF) ln([X]2/[X]1)
• EX is the equilibrium potential for ion X, R is the gas constant, T is absolute temperature (Kelvin), z is the valence of the ion, and F is the Faraday constant

Simplified Nernst Equation

• Simplified for easier calculation at room temperature: EX = (58/z) log([X]2/[X]1)

Applying Nernst

• For the example in Figure 2.4B, the potential across the membrane at electrochemical equilibrium is EK = 58 log(1/10) = -58 mV
• Equilibrium potential is defined by the potential difference between the reference compartment (side 2) and the other side
• The outside of the cell is the conventional reference point (defined as zero potential)

Hypothetical System

• In a system with only one permeant ion species, the Nernst equation allows exact prediction of the equilibrium electrical potential
• If the K+ concentration on side 1 is increased to 100 mM, the membrane potential becomes –116 mV
• When the membrane potential is plotted against the logarithm of the K+ concentration gradient ([K]2/[K]1), the Nernst equation predicts a linear relationship with a slope of 58 mV per tenfold change in the K+ gradient

Experiments on Influence of Ionic Species

• Replacing potassium on side 2 with 10 mM sodium (Na+) and replacing K+ in compartment 1 with 1 mM Na+, no potential is generated because no Na+ can flow across the membrane
• Replacing the K+-permeable membrane with a membrane permeable only to Na+, a potential of +58 mV would be measured at equilibrium

Calcium and Chloride

• If 10 mM calcium (Ca2+) were present in compartment 2 and 1 mM Ca2+ in compartment 1, a Ca2+-selective membrane would develop a potential of +29 mV
• If 10 mM Cl– were present in compartment 1 and 1 mM Cl– in compartment 2, a Cl–-permeable membrane would produce a potential of +58 mV

Influence of Membrane Potential on Ionic Flux

• Connecting a battery across the membrane controls the electrical potential without changing ion distribution
• With the battery off, K+ flows from compartment 1 to compartment 2, causing a negative membrane potential.
• Making compartment 1 initially more negative reduces K+ flux
• At –58 mV, there is no net flux of K+
• Making compartment 1 more negative than –58 mV causes K+ to flow from compartment 2 into compartment 1
• This demonstrates that both the direction and magnitude of ion flux depend on the membrane potential

Importance

• The ability to alter ion flux experimentally by changing either the potential imposed on the membrane or the transmembrane concentration gradient
• Provides tools for studying ion fluxes across neuronal plasma membranes

Multiple Permeant Ion Environment

• Consider an environment where Na+ and K+ are unequally distributed in Figure 2.6A
• With 10 mM K+ and 1 mM Na+ in compartment 1, and 1 mM K+ and 10 mM Na+ in compartment 2
• If the membrane were permeable only to K+, the membrane potential would be –58 mV
• if the membrane were permeable only to Na+, the potential would be +58 mV

Permeability

• If permeable to both K+ and Na+, the potential depends on the membrane's relative permeability to each
• More permeable to K+, potential approaches –58 mV
• More permeable to Na+, potential nears +58 mV

Goldman Equation

• Developed by David Goldman in 1943
• V = 58 log((PK[K]2 + PNa[Na]2 + PCl[Cl]1) / (PK[K]1 + PNa[Na]1 + PCl[Cl]2))
• Considers concentration gradients and relative permeability of permeant ions (K+, Na+, and Cl–)
• An extended version of the Nernst equation that takes into account the relative permeabilities of each of the ions involved
• Simplifies to the Nernst equation when the membrane is permeable only to one ion (e.g., K+)
• Negative charged chloride ions, Cl–, have been inverted relative to the concentrations of the positively charged ions
• remember that –log (A/B) = log (B/A)

Applying the Goldman Equation

• If the membrane in Figure 2.6A is permeable to K+ and Na+ only
• terms involving Cl– drop out because PCl is 0
• Solution yields a potential of –58 mV when only K+ is permeant, +58 mV when only Na+ is permeant, and some intermediate value if both ions are permeant For example, if K+ and Na+ were equally permeant, then the potential would be 0 mV

Neural Signaling

• What happens if the membrane starts permeable to K+, then switches to Na+?
• Starts negative, becomes positive while Na+ permeability is high, then returns to negative as Na+ permeability decreases
• Essentially describes a neuron during an action potential generation

Resting State Scenario

• PK of the neuronal plasma membrane is much higher than PNa
• Always more K+ inside the cell than outside (Table 2.1), the resting potential is negative (Figure 2.6B).
• Depolarization increases PNa, and a transient increase in Na+ permeability causes the membrane potential to become even more positive
• Na+ rushes in (more Na+ outside), leading to an action potential
• The rise in Na+ permeability during the action potential is transient
• As membrane permeability to K+ is restored, the membrane potential quickly returns to its resting level

Ion Transporters Role

• Maintained transmembrane gradients for most ions

Squid Neuron

• Basis for stating that there is much more K+ inside the neuron than out, and much more Na+ outside than in

Mammalian Neuron

• The concentrations of each ion are several times lower than squid neuron
• These transporter-dependent concentration gradients are, indirectly, the source of the resting neuronal membrane potential and the action potential

Nernst on Gradients

• Once the ion concentration gradients across various neuronal membranes are known, the Nernst equation can be used to calculate the equilibrium potential for K+ and other major ions resting membrane potential of the squid neuron is approximately –65 mV, K+ is the ion that is closest to being in electrochemical equilibrium when the cell is at rest This implies that the resting membrane is more permeable to K+ than to the other ions listed in Table 2.1, and that this permeability is the source of resting potentials

Experiments Modifying K+ Concentration

• Changing K+ concentration impacts resting membrane potential
• Altering the concentration of K+ outside the neuron
• Validating this hypothesis, Alan Hodgkin and Bernard Katz asked what happens to the resting membrane potential if the concentration of K+ outside the neuron is altered
• If the resting membrane were permeable only to K+, then the Goldman equation (or even the simpler Nernst equation) predicts that the membrane potential will vary in proportion to the logarithm of the K+ concentration gradient across the membrane
• Assuming that the internal K+ concentration is unchanged during the experiment, a plot of membrane potential against the logarithm of the external K+ concentration should yield a straight line with a slope of 58 mV per tenfold change in external K+ concentration at room temperature

Resting Experiment Conclusions

• Hodgkin and Katz found that the resting membrane potential changed when the external K+ concentration was modified, becoming less negative as external K+ concentration was raised
• When the external K+ concentration was raised high enough to equal the concentration of K+ inside the neuron, the resting membrane potential was also approximately 0 mV
• Hodgkin and Katz rested membrane potential varied as predicted with the logarithm of the K+ concentration, with a slope that approached 58 mV per tenfold change in K+ concentration
• Manipulation of the external concentrations of these other ions has only a small effect, emphasizing that K+ permeability is indeed the primary source of the resting membrane potential

K+ Conclusion

• Hodgkin and Katz showed that the inside-negative resting potential arises because:
• the membrane of the resting neuron is more permeable to K+ than to any of the other ions present
• there is more K+ inside the neuron than outside
• Neurons' membranes are selectively permeable to K+
• Large K+ concentration gradient is produced by membrane transporters that selectively accumulate K+ within neurons

Action Experiment

• Hodgkin and Katz hypothesized that the action potential arises because the neuronal membrane becomes temporarily permeable to Na+
• Hodgkin and Katz tested the role of Na+ in generating the action potential by asking what happens to the action potential when Na+ is removed from the external medium

Action Experiment Findings

• Lowering external Na+ concentration reduces both the rate of rise of the action potential and its peak amplitude
• Linear relationship between the amplitude of the action potential and the logarithm of the external Na+ concentration
• While the resting neuronal membrane is only slightly permeable to Na+, the membrane becomes extraordinarily permeable to Na+ (action potential nomenclature)

Na+ Channels

This temporary increase in Na+ permeability results from the opening of Na+-selective channels that are essentially closed in the resting state Membrane pumps maintain a large electrochemical gradient for Na+, which is in much higher concentration outside the neuron When the Na+ channels open, Na+ flows into the neuron, causing the membrane potential to depolarize and approach ENa.

Overshoot Phase

• The time that the membrane potential lingers near ENa (about +58 mV) during the overshoot phase of an action potential is brief because the increased membrane permeability to Na+ itself is short-lived
• The membrane potential rapidly repolarizes to resting levels and is actually followed by a transient undershoot
• Inactivation of the Na+ permeability and an increase in the K+ permeability of the membrane
• During the undershoot, the membrane potential is transiently hyperpolarized because K+ permeability becomes even greater than it is at rest
• The action potential ends when this phase of enhanced K+ permeability subsides, and the membrane potential thus returns to its normal resting level

Experimental Evidence

• Resting membrane potential results from a high resting membrane permeability to K
• Depolarization during an action potential results from a transient rise in membrane Na+ permeability
• Experiments didn't establish how neuronal membrane changes its ionic permeability or what mechanisms trigger it

Summary Points

• Nerve cells generate electrical signals to convey information over substantial distances and to transmit it to other cells using synaptic connections

• Resting potential occurs due to nerve cell membranes' selective permeability to ion species under electrochemical gradients

• Negative resting membrane potential results from net K+ efflux across membranes mainly permeable to K+

• Action potential occurs with transient Na+ permeability increase, enabling net Na+ flow in the opposite direction across a predominantly Na+-permeable membrane

• Brief Na+ permeability rise is followed by secondary K+ permeability rise, repolarizing the membrane and causing a brief undershoot

• These processes lead to "all-or-none" depolarization during an action potential

• Membrane potential returns to its resting level due to high K+ permeability when active permeability changes subside