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ARTICLE in PRACTICAL NEUROLOGY · JULY 2007 Source: PubMed

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Available from: Mark W Barnett Retrieved on: 24 October 2015 192 Practical Neurology

HOW TO UNDERSTAND IT Pract Neurol 2007; 7: 192–197 The action potential Mark W Barnett, Philip M Larkman

t is over 60 years since Hodgkin and called channels that form the permeation Huxley1 made the first direct recording of pathways across the neuronal membrane. the electrical changes across the neuro- Although the first electrophysiological nal membrane that mediate the action recordings from individual ion channels were I 2 potential. Using an electrode placed inside a not made until the mid 1970s, Hodgkin and giant they were able to measure a Huxley predicted many of the properties now transmembrane potential of around 260 mV known to be key components of their inside relative to outside, under resting function: ion selectivity, the electrical basis conditions (this is called the resting mem- of -sensitivity and, importantly, a brane potential). The action potential is a mechanism for quickly closing down the transient (,1 millisecond) reversal in the permeability pathways to ensure that the polarity of this transmembrane potential action potential only moves along the axon in which then moves from its point of initiation, one direction. down the axon, to the axon terminals. In a M W Barnett subsequent series of elegant experiments ION DISTRIBUTION AND THE Post-doctural Research Fellow Hodgkin and Huxley, along with Bernard RESTING Centre for Integrative , Katz, discovered that the action potential The resting membrane potential is essential School of Biomedical Sciences, results from transient changes in the perme- for the normal functioning of the and University of Edinburgh, Edinburgh, + ability of the axon membrane to (Na ) is maintained through an unequal distribution UK + + and (K ) . Importantly, Na and of ions across the neuronal membrane. + P M Larkman K cross the membrane through independent Figure 1A:i illustrates the distribution of ions Lecturer pathways that open in response to a change across the membrane of a typical neuron. The Centre for Research, in membrane potential. different ion concentrations are established School of Biomedical Sciences, As testimony to their pioneering work, the and maintained by ATP-dependent pumps, University of Edinburgh, Edinburgh, fundamental mechanisms described by most significantly one that exchanges inter- UK Hodgkin, Huxley and Katz remain applicable nal Na+ for external K+, thereby concentrating to all excitable cells today. Indeed, the Na+ outside, and K+ inside, the neuron. Correspondence to: predictions they made about the molecular Dr M W Barnett Consider what happens if membrane perme- + Centre for Integrative Physiology, mechanisms that might underlie the changes ability to Na ions suddenly increases. What + School of Biomedical Sciences, in membrane permeability showed remarkable forces act on the Na ions? The high external + University of Edinburgh, Edinburgh foresight. The molecular basis of the action concentration of Na means there is a EH8 9XD, UK; [email protected] potential lies in the presence of concentration gradient. Na+ diffuses down 193

Figure 1 (Ai) Diagrammatic representation of the unequal distribution of ions across a typical neuronal membrane. All concentrations are in millimolar (mM) except where indicated otherwise. Internal and external Na+ and K+ concentrations are maintained by the ATP-dependent Na+/K+ pump. A- represents the large internal anionic charge carried by non- membrane permeable proteins. Cytoplasmic Ca2+ is usually maintained at nanomolar (1029M) concentrations by sequestration into membrane localised stores. The resting membrane potential (Vrest = 260 to 270 mV) is measured inside the neuron relative to outside. (A:ii) The used to determine the equilibrium potential (E) for the ion, x, where R is the , T is the temperature in˚K, F is the Faraday constant and zx is the valency of ion, x.[X]o and [X]i are the external and internal concentrations of ion x, respectively. (B) Illustration of the membrane potential changes resulting from either an increase in conductance to Na+ (gNa+)orK+ (gK+). The change in membrane potential is determined by the difference between the resting membrane potential (Vrest) and the equilibrium potential for that ion (ENa+ or EK+). (Ci), a two dimensional, diagrammatic, representation of the molecular structure of the pore forming a subunit of the voltage-sensitive Na+ channel. It is a single that has four domains (I, II, III, IV). Each domain has six transmembrane (TM) spanning regions (1–6). The region between the TM5 and TM6 in each domain dips into the membrane but does not cross fully before coming back out on the extracellular side. These are called the P-loops (coloured magenta). Voltage-sensitivity is conferred predominantly by TM4 (green) in each domain. Each TM4 contains several positively charged amino-acid residues(++++). A change in voltage across the membrane promotes a movement of TM4 that induces a conformational change, opening the channel pore. The linker region between domains III and IV (blue) forms the inactivation gate. (Cii) A proposed 3D view through the voltage-sensitive Na+ channel. Each of the domains forms the outside of a cylindrical structure with a central pore, lined by TM6 of each domain. The P-loops (magenta) form a selectivity filter at the extracellular entrance to the channel that determines which ions pass through the channel. Movement of the voltage (TM4) is thought to induce movements of the intracellular ends of TM6 in the direction indicated by the red arrows thereby opening the activation gate. The blue arrow indicates themovementofthe inactivation gate resulting in blockage of the open pore from the intracellular side. this concentration gradient into the neuron membrane potential also has an effect on carrying with it a net positive electrical the movement of Na+ ions. As the electrical charge. The movement of positive charge gradient across the membrane is diminished it makes the inside of the neuron more positive starts to oppose the movement of the (known as depolarisation) leading to a positively charged ions into the . Thus, reduction and eventual reversal of the two opposing forces act on the Na+ ion—a transmembrane potential. This change in concentration gradient and an electrical

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Figure 2 A diagrammatic representation of the action potential and associated models depicting the sequence of activation and inactivation of the voltage- sensitive Na+ and K+ channels. Arrows indicate the state of the respective ion channels during different phases of the action potential. The broken line on the action potential trace indicates the resting membrane potential and is used to highlight the rebound after- hyperpolarisation.

gradient. These two forces will eventually IONIC PERMEABILITY CHANGES reach equilibrium at a new, stable, membrane UNDERLYING THE ACTION potential. This is called the equilibrium POTENTIAL potential for Na+, defined as the membrane The action potential can be divided into three potential at which there is no net flow of Na+ main phases. The initial phase is a rapid change across the membrane. The equilibrium poten- in membrane potential from around 260 to tial can be determined from the Nernst +40 mV (depolarisation). The second phase is a equation (fig 1Aii). Thus, for our typical ionic return towards the resting membrane potential concentrations, equilibrium potentials for Na+ (repolarisation), and the third phase is a slowly and K+ would be +55 mV and 2103 mV at recovering overshoot of the , 37˚, respectively. termed the after-hyperpolarisation (fig 2). The What determines the resting membrane initial depolarising phase is mediated by an potential? At rest the neuronal membrane is increase in membrane permeability to Na+.If permeable to several ions, thus, the resting Na+ is removed from the extracellular solution, potential is not equivalent to the equilibrium action potentials cannot be generated and potential of any one ion but lies between the the membrane current that underlies the equilibrium potentials for the individual ions. depolarisation from 260 to +40 mV is If K+ permeability dominates, the resting abolished. This has been confirmed using potential will be close to the K+ equilibrium (TTX), a found in the potential. If permeability to K+ and Na+ is ovaries and liver of the puffer fish, which, by equal, the resting potential will lie between potently blocking Na+ channels, abolishes the equilibrium potentials for these ions. This action potentials in . means, that when additional ion channels In Hodgkin and Huxley’s original experi- open, the direction of ion movement and, ments they initiated an action potential by therefore, the change in membrane potential, applying a very short electrical current to the will be determined by the difference between outside of the . This promotes a local, the resting membrane potential and the depolarising disturbance in the resting mem- equilibrium potential for that ion or ions brane potential that induces the opening of a (fig 1B). small number of Na+ channels generating 195 what is termed a ‘‘local depolarising response’’ channel is the result of another part of of the membrane. But what normally triggers the channel that an action potential? In sensory neurons occludes the pore and so prevents further + stimulation of specialised end- movement of Na . The pore blocking ings may lead to a local depolarising response. structure is termed the inactivation gate. At a molecular level the inactivation gate In the central , synaptic events is a part of the channel that is found on received over the dendritic tree of a neuron are the intracellular side of the membrane integrated into a that may be sufficient that flips up and occludes the inner to promote the generation of action potentials entrance to the pore (fig 1Ci and ii). in the axon of the neuron. Na+ channels open because they possess a N The second reason for the termination of mechanism that detects depolarisation the depolarisation is the opening of in transmembrane voltage. Triggering this another set of voltage-sensitive channels sensor promotes their opening, or activation, in the membrane. These channels are + through a conformational change in a part of selectively permeable to K ions. As we + the close to the inner face of the have seen already, the intracellular K concentration is high resulting in an membrane, commonly termed the activation equilibrium potential more negative than ‘‘gate’’ (fig 1Cii). This is why Na+ channels are the resting membrane potential. Thus, said to be voltage-sensitive (‘‘voltage-gated’’ or when the membrane potential is depo- ‘‘voltage-activated’’ are synonymous terms). A larised during the action potential, K+ + few Na channels open in response to the local flows out of the neuron bringing the depolarisation and the influx of Na+ through membrane potential back towards more these channels then adds to the depolarisation. negative potentials. Two properties tailor If the membrane potential depolarises to a these voltage-sensitive K+ channels to this ‘‘threshold’’ value around 245 mV, then there role; compared to Na+ channels, they will be a rapid recruitment of all the voltage- require a greater depolarisation of the sensitive Na+ channels leading to the fast membrane potential before they open, and depolarising phase of the action potential. This they activate more slowly (over several milliseconds) than Na+ channels. These recruitment of Na+ channels is ‘‘regenerative’’ properties allow the depolarising phase of in the that Na+ going through one the action potential to be initiated before channel adds to the depolarisation which the K+ channels open (fig 2). triggers more Na+ channels to open. As such, + the action potential is termed an ‘‘all or Thus, an increase in K permeability initially nothing’’ response; once threshold is reached puts a brake on the depolarising phase of the + the full action potential is always generated. action potential and then, as all the K + The molecular mechanisms which have been channels activate and the Na channels start proposed to underlie voltage-sensitivity and to inactivate, the membrane potential is the subsequent opening of the activation gate driven back towards the resting state. This + are illustrated in figure 1Ci and ii. K conductance is termed the ‘‘Delayed + The depolarising phase of the action ’’ K conductance because it activates potential overshoots zero mV so reversing after, and it repolarises or ‘‘rectifies’’ the the transmembrane potential; however, the change in membrane potential caused by the + depolarisation stops before it reaches the opening of Na channels. In addition, the + predicted equilibrium potential for Na+. This is channel does not inactivate, thus K perme- for two reasons: ability is terminated by closing the activation gate, or deactivation, as the membrane N The first is an inherent property of potential hyperpolarises. This process is, voltage-gated Na+ channels, known as however, slow (like the opening of K+ inactivation. After being open for only a channels) which means these channels very short time (,1 millisecond), the Na+ channel switches to a conformation that remain open for a period after the action no longer allows Na+ to pass through potential and this can result in an overshoot even though the membrane potential is of the resting membrane potential, generating still depolarised and the activation gate is what is termed an after-hyperpolarisation. still open (fig 2). This conformation of the We will return to this shortly. www.practical-neurology.com 196 Practical Neurology

HOW DOES THE ACTION greater penetration down the core of the axon. POTENTIAL PROPAGATE DOWN But even with the insulating there is a THE AXON? limit to how far a local current can propagate The depolarisation of the membrane by the in the absence of high densities of Na+ action potential generates local currents that channels, thus, at intervals down the axon, depolarise adjacent parts of the axon mem- gaps in this myelin sheath called ‘‘nodes of brane. If these local currents depolarise the Ranvier’’ are found. The density of voltage- adjacent membrane to threshold, the action gated channels in the axonal membrane is high potential will be propagated to this part of the at these nodes to allow the action potential to membrane and so on down the axon. The speed propagate by jumping from node to node by at which the action potential propagates down what is called ‘‘’’ (from the the axon, or conduction velocity, is largely the Latin meaning ‘‘to jump’’). result of how far the local currents extend down the axon before an action potential is WHY DOES THE ACTION produced. The further the local currents travel POTENTIAL ONLY PROPAGATE IN down the axon, while being of sufficient ONE DIRECTION ALONG THE amplitude to still allow the membrane to reach AXON? threshold, the faster the propagation of the Action potentials usually propagate from the action potential. This distance depends on the cell body, down the axon, to the axon terminals. electrical properties of the axon, in particular This polarity is largely due to the action the electrical resistance of the membrane and potential being triggered by synaptic input the internal contents of the axon. Large received across the dendritic tree of the neuron. diameter have low internal resistance Action potentials do not normally propagate while the greater the number of open channels back into the because, in general, in the membrane, the lower the membrane they do not have a sufficiently high density of resistance. High internal resistance and low voltage-sensitive Na+ channels. However, once membrane resistance will result in slow the action potential reaches the axon terminals propagation of the action potential. what prevents it turning round and coming A commonly used analogy for the spread of back up the axon? Remember, that after the these local currents is a leaky garden hose. initial depolarising phase of the action poten- Water pushing down the hose follows the path tial, voltage-gated Na+ channels are in an of least resistance; thus, if the diameter is inactivated state. This inactivation means that narrow and there are many holes, water leaks once an action potential has occurred, that part out limiting the distance it can travel down the of the membrane enters a period during which core of the hose. There are two solutions to another action potential cannot be initiated. getting water further down the hose. Either, Thus, the action potential propagates towards increase the diameter of the hose thereby the axon terminals because only the membrane making the core a lower resistance pathway, or ‘‘ahead’’ of it has Na+ channels ready to open. patch up the holes in the hose with tape The axon ‘‘behind’’ the action potential, where it thereby preventing leakage. The squid adopts has just come from, has inactivated Na+ the first solution with axon diameters of channels so cannot generate another action ,1 mm. The second alternative is preferred potential until these channels recover from the by the mammalian inactivated state, a process which is both time- where the number of neurons is greater and and voltage-dependent, occurring faster at space at a premium. Specialised glial cells hyperpolarised potentials. The membrane called wrap themselves ‘‘behind’’ the action potential is said to be around the axon to form a high resistance ‘‘refractory’’. Indeed, because the Na+ channels insulating membrane called the myelin sheath areunabletoconductNa+ in this state, an (in the peripheral nervous system myelination action potential cannot be generated no matter is provided by another type of glial cell, the how big the local membrane depolarisation. ). Thus, the local currents are The time during which no action potential can unable to leak across the membrane because be generated is termed the ‘‘absolute refractory of the insulating myelin, resulting in their period’’. 197

In addition, for a short time, the axon WHAT HAPPENS WHEN THINGS membrane ‘‘behind’’ the action potential, has GO WRONG? high permeability to K+ because K+ channels Action potentials are fundamental for neuro- close relatively slowly. Open K+ channels nal communication, their frequency and mediate the after-hyperpolarisation (fig 2) pattern being the code for information transfer and also confer low membrane resistance, throughout the nervous system. There are 10 conditions which oppose the chance of distinct types of mammalian Na+ channel and reaching threshold. This also contributes to more than 90 K+ channel types, each with the reluctance of the membrane ‘‘behind’’ the subtly different properties. Different neuronal action potential to initiate another action types have different channel combinations, potential. The transient after-hyperpolarisa- therefore, the frequencies at which they tion, however, speeds up the recovery of Na+ conduct action potentials vary greatly. In the channels from inactivation. Therefore, once peripheral nervous system sensory neurons enough Na+ channels have recovered from conduct action potentials at frequencies inactivation, an action potential can be between 1 and 20/second. In the central initiated but a greater stimulus is required nervous system, there are many examples of because the K+ permeability is still high. This neuronal types coding action potentials at period is termed the ‘‘relative refractory these frequencies but there are others that can period’’. generate must faster bursts of action poten- By the time Na+ channels have recovered tials. For example, the Purkinje cells of the from inactivation and K+ channels have can generate action potentials up closed, the action potential will have moved to 200/second while some neurons in the a distance away from this part of the axon , thalamus and cortex can pro- membrane such that the local currents that duce action potential bursts of up to 300/ spread back (and the depolarisation they second. It is not surprising then that disrupting cause) will not be big enough to reach the mechanisms that underlie this signalling threshold. This ensures that in response to a system can have disastrous consequences. In single stimulus an action potential only several forms of epilepsy the characteristic propagates in one direction—down, not up, hyperexcitability of neurons that mediates the axon. Another action potential can only seizure activity can be attributed to mutations be generated by further stimulation after an that alter the normal function of voltage- interval determined by Na+ channel inactiva- sensitive Na+ or K+ channels (see Ashcroft for tion and relatively slow K+ channel closure. review).3 In a similar way, changes in sensory Therefore, these properties also tightly govern neuron excitability associated with some the maximum frequency at which an axon chronic states may be attributable to can generate action potentials. changes in voltage-sensitive ion channel It is worth noting, however, that if the function. Finally, the symptoms associated stimulus that triggers the action potential with are linked to impaired occurs at the axon terminals then an action action potential propagation caused by a potential will propagate towards the cell disruption of axon myelination. body. We might do this experimentally in Thus, the mechanisms first described over which case we would call it an ‘‘’’ 60 years ago remain vital to our continued action potential. Also, sensory with progress in the understanding of a range of specialised axon terminals that act as disorders. receptors in the skin propagate action potentials towards, rather than away from, REFERENCES the cell body, but again only in one direction. 1. Hodgkin AL, Huxley AF. Action potentials recorded from inside a nerve fibre. Nature Thus, the properties of the channels that 1939;144:710–11. mediate the action potential do not confer a 2. Neher EJ, Sakmann B. Single channels currents direction of propagation on the axon per se recorded from the membrane of denervated muscle fibres. Nature 1976;260:779–802. but do ensure that an action potential only 3. Ashcroft FM. From molecule to malady. Nature propagates away from the stimulus source. 2006;440:440–7.

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