Effect of Hyperkalemia on Membrane Potential: Depolarization

❖ CASE 3 A 6-year-old boy is brought to the family physician after his parents noticed that he had difficulty moving his arms and legs after a soccer game. About 10 minutes after leaving the field, the boy became so weak that he could not stand for about 30 minutes. Questioning revealed that he had complained of weakness after eating bananas, had frequent muscle spasms, and occasionally had myotonia, which was expressed as difficulty in releasing his grip or difficulty opening his eyes after squinting into the sun. After a thorough physical examination, the boy was diagnosed with hyperkalemic periodic paralysis. The family was advised to feed the boy carbohydrate-rich, low-potassium foods, give him glucose-containing drinks during attacks, and have him avoid strenuous exercise and fasting. ◆ What is the effect of hyperkalemia on cell membrane potential? ◆ What is responsible for the repolarizing phase of an action potential? ◆ What is the effect of prolonged depolarization on the skeletal muscle Na+ channel? 32 CASE FILES: PHYSIOLOGY ANSWERS TO CASE 3: ACTION POTENTIAL Summary: A 6-year-old boy who experiences profound weakness after exercise is diagnosed with hyperkalemic periodic paralysis. ◆ Effect of hyperkalemia on membrane potential: Depolarization. ◆ Repolarization mechanisms: Activation of voltage-gated K+ conductance and inactivation of Na+ conductance. ◆ Effect of prolonged depolarization: Inactivation of Na+ channels. CLINICAL CORRELATION Hyperkalemic periodic paralysis (HyperPP) is a dominant inherited trait caused by a mutation in the α subunit of the skeletal muscle Na+ channel. It occurs in approximately 1 in 100,000 people and is more common and more severe in males. The onset of HyperPP generally occurs in the first or second decade of life. HyperPP is neither painful nor life-threatening but can be dis- ruptive to normal activities. Symptoms are muscle weakness and paralysis, sometimes preceded by myotonia, fasciculations, or spasms. Fortunately, significant paralysis almost never occurs in intercostals or diaphragm muscles, and so breathing is not impaired. Attacks can occur spontaneously but often are triggered by exercise, stress, fasting, or the ingestion of large quantities of K+ (eg, in bananas). For unknown reasons, exercise-induced paralysis always follows exercise—it does not occur during exercise. Because exercise can pro- duce hyperkalemia and hyperkalemia triggers HyperPP attacks, there must be an additional mechanism that protects skeletal muscle during but not after intense activity. The mechanisms that underlie the effects of HyperPP result from several known mutations in the α subunit of the skeletal muscle Na+ channel that prevent it from closing effectively. Ineffective closing results in a small, persistent inward current that continuously depolarizes the muscle membrane; this lowers the action potential threshold, producing the hyperex- citability that results in fasciculations (spontaneous twitches) and spasms under resting conditions. If the depolarization increases further, as occurs when extracellular [K+] is elevated, the Na+ channels inactivate and remain inactivated until repolarization occurs. This inactivation blocks action potential initiation in the muscle and produces paralysis. When extracellular [K+] decreases, the depolarization is reduced, inactivation is removed, and the paralysis is relieved. Amelioration of HyperPP attacks is attempted by reduc- ing plasma K+ levels. Insulin promotes the transport of extracellular K+ into intracellular compartments by activating the Na-K pump. Eating high- carbohydrate diets or pure glucose increases insulin secretion and thus decreases extracellular [K+]. Conversely, fasting decreases insulin secretion and can elevate extracellular [K+], increasing the chances of myotonia and paralysis in HyperPP patients. CLINICAL CASES 33 APPROACH TO ACTION POTENTIAL PHYSIOLOGY Objectives 1. Know the mechanisms of the resting potential. 2. Understand the mechanisms of the action potential in axons and skeletal muscle. Definitions Action potential: A rapid, depolarizing change in membrane potential (often overshooting, so that the potential transiently reverses) that is used by excitable cells to convey all-or-none electrical signals quickly from one point on the cell to the remainder of the cell. Electrotonic conduction: The passive, exponentially falling, spread of a difference in membrane potential between different membrane regions, which occurs with potentials subthreshold for an action potential or with perturbations of membrane potential in inexcitable membrane regions. Nernst equilibrium potential: The membrane potential at which, for a given ion, there is no net flow of the ion across the membrane, which corresponds to the electrical force that exactly offsets the driving force of the concentration gradient acting on that ion. Resting potential: The electrical potential difference across the plasma membrane in the absence of action potentials or synaptic potentials. Voltage-gated channel: Pore-forming protein complexes that allow ions to flow across a membrane, and which can be opened (or, in some cases, closed) by a change in membrane potential. DISCUSSION The mechanisms that underlie the action potential cannot be understood with- out an understanding of how a resting membrane potential is generated. The resting potential in nearly all mammalian cells is produced primarily by dif- fusion of K+ down its concentration gradient from inside to outside the cell, whereas the membrane remains relatively impermeable to other ions. The intracellular concentration of K+ is very high compared with the outside concentration because K+ is pumped into the cell by the Na+-K+-ATPase (adenosine triphosphatase) (see Figure 3-1). Because the membrane is effectively impermeable to intracellular anions, as K+ flows down its concentration gradient, it leaves behind anions. A transmembrane potential (Vm) develops as the K+ efflux brings a positive charge to the region just outside the membrane, leaving an equal amount of negative charge just inside the membrane. This process is self-limiting because as soon as a membrane becomes permeable to K+ and K+ efflux begins, the resulting separation of the charge generates an electrical driving force on the ions, and the electrical driving 34 CASE FILES: PHYSIOLOGY 2K+ β Outside α 3Na+ Inside Figure 3-1. Na+-K+-ATPase pump. The α subunit is the catalytic subunit, which uses adenosine triphosphate (ATP) for energy to drive the extrusion of three Na+ ions for every two K+ ions taken into the cell. The β subunit is important for assembly and membrane targeting of the Na+-K+-ATPase. Pump activity can be blocked by cardiac glycosides, such as ouabain. (From Horisberger JD, Lemas V, Kraehenbuhl JP, Rossier BC. Structure–function relationship of Na-K-ATPase. Ann Rev Physiol. 1991;53:565. Reproduced, with permission, from the Annual Review of Physiology, vol. 53. Copyright © 1991 by Annual Reviews Inc.) force soon equals the opposing chemical driving force (the K+ concentration + gradient). For K or any ion X, this equilibrium occurs at a Vm called the Nernst equilibrium potential, which is defined as the electrical driving force (EX) that exactly offsets the chemical driving force. The electrical driving force is represented by the left side and the chemical driving force is represented by the right side of the Nernst equation: RT []X = o EX In zF []X i R is the gas constant, T is the temperature in degrees Kelvin, z is the valence of the ion, F is the Faraday constant, and [X]o and [X]i are the ion’s extracellular and intracellular concentrations. In the case of K+ at 37°C and converting to log10, the equation becomes []K+ = o Ek 60 log + []K i It is important to note that a given ion X is at equilibrium across the membrane = only when Vm EX. Because of the relatively high intracellular concentrations CLINICAL CASES 35 + ∼− of K in mammalian cells, EK is always quite negative (eg, 90 mV). Because of the pumping action of the Na+-K+-ATPase, the concentration gra- + + + = dient for Na is in the opposite direction (ie, [Na ]o >> [Na ]i), and thus ENa ∼+55 mV. However, in cells, such as glia, in which there is no significant per- + + meability to Na ,Na influx makes almost no contribution to Vm. ≠ In most cells, including all excitable cells, Vm EK, although the values are often close. This is the case because the membrane is also permeable to other ions, and it is the net effect of all ion permeability across the membrane that determines Vm. In many axons, Vm is determined almost entirely by opposing fluxes (or, in electrical terms, currents) carried by K+ and Na+. These can be α= described, in terms of the ratio of permeabilities ( PNa/PK) and ionic concentrations, by the Goldman-Hodgkin-Katz equation, which is closely related to the Nernst equation: []KNa+++ α [ ] V = 60 log oo m +++ α []KNaio [ ] In an axon at rest, α=approximately 0.01, and so the contributions of the Na+ ∼− concentrations in the expression are slight, and Vm is close to EK ( 90 mV). In many neuronal cell bodies or dendrites, PNa is somewhat greater than this when ∼− the cell is at rest and Vm is more depolarized (eg, 65 mV). Permeabilities (P) often are referred to by their electrical equivalents, conductances (g). Note that an increase in extracellular K+, that is, hyperkalemia, will depolarize cells, whereas hypokalemia will hyperpolarize cells. An all-or-none action potential is generated in an axon when membrane depolarization reaches a level at which voltage-gated Na+ channels open, + increasing PNa. This results in an inward current of Na , which causes further depolarization, which then opens additional Na+ channels. This regenerative (positive feedback) cycle quickly produces an overshooting action potential. In terms of the Goldman-Hodgkin-Katz equation, α quickly goes from + approximately 0.01 to 100, Vm becomes dominated by the Na concentration gradient, and thus Vm approaches ENa at the peak of the action potential. Axonal action potentials last only a few milliseconds because two mechanisms rapidly repolarize the membrane.

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