Generation of resting membrane potential

Stephen H. Wright Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona 85724 IT WOULD BE DIFFICULT TO EXAGGERATE the physiological significance of the transmembrane electrical potential difference (PD). This gradient of electrical energy that exists across the plasma membrane of every cell in the body influences the transport of a vast array of nutrients into and out of cells, is a key driving force in the movement of salt (and therefore water) across cell membranes and between organ-based compartments, is an essential element in the signaling processes associated with coordinated movements of cells and organisms, and is ultimately the basis of all cognitive processes. For those reasons (and many more), it is critical that all students of physiology have a clear understanding of the basis of the resting membrane potential (so called to distinguish the steadystate electrical condition of all cells from the electrical transients that are the action potentials of excitable cells: i.e., neurons and muscle cells). How, then, does this electrical gradient arise? It is the consequence of the influence of two physiological parameters: 1) the presence of large gradients for K+ and Na+ across the plasma membrane; and 2) the relative permeability of the membrane to those ions. The gradients for K+ and Na+ are the product of the activity of the Na+-K+-ATPase, a primary active ion pump that is ubiquitously expressed in the plasma membrane of (for all intents and purposes) all animal cells. This process develops and then maintains the large outwardly directed K+ gradient, and the large inwardly directed Na+ gradient, that are hallmarks of animal cells. For the purpose of this discussion, we will assume that the requisite gradients are in place (acknowledging that the mechanism of ion transport is beyond the scope of this presentation). The second parameter, the relative permeability of the plasma membrane to Na + and K+, reflects the open versus closed status of ion-selective membrane channels. Importantly, cell membranes display different degrees of permeability to different ions (i.e., permselectivity), owing to the inherent selectivity of specific ion

channels. The combination of 1) transmembrane ion gradients, and 2) differential permeability to selected ions, is the basis for generation of transmembrane voltage differences. This idea can be developed by considering the hypothetical situation of two solutions separated by a membrane permselective to a single ionic species. Side 1 (the inside of our hypothetical cell) contains 100 mM KCl and 10 mM NaCl. Side 2 (the outside) contains 100 mM NaCl and 10 mM KCl. In other words, there is an outwardly directed K+ gradient, and inwardly directed Na+ gradient, and no transmembrane gradient for Cl-. For the purpose of this discussion, this ideal permselective membrane is permeable only to K+.

The electrochemical driving force (ECDF). Membrane potential (Vm) is the separation of charges across a cell membrane and is established by the selective permeability of the membrane and the active transport of ions across it. The result is a differential distribution of ions and an excess of negative charge on the membranes inner surface. For any ion, X, present in unequal concentrations across the membrane, there are two forces acting on it. First, there is a chemical driving force (CDF) resulting from the concentration gradient. Second, there is an electrical driving force (EDF) resulting from the interaction between the charge of the ion and Vm. If these forces are equal in magnitude but opposite in direction, there will be no net, or electrochemical, driving force acting on that ion (Fig. 1A). Under these conditions, ion X will be in electrochemical equilibrium and will exhibit no net flux in either direction across the membrane. The membrane potential that exactly balances the CDF, thus establishing electrochemical equilibrium, is obtained from the Nernst equation E x = (RT/zF)ln(Xe/Xi) where Ex is the equilibrium potential for ion X, R is the gas constant, T is the absolute temperature, z is the valance of ion X, F is the Faraday constant, Xe the extracellular concentration of X, and Xi the intracellular concentration of X.

Converting to log base 10 for a monovalent ion at 18C, the Nernst equation reduces to

E x = 58 log(Xe/Xi) If Vm does not equal Ex, then X will be out of electrochemical equilibrium and there will exist an ECDF equal in magnitude to the difference between Vm and E x (ECDF)x = Vm - Ex This will result in a net passive flux of X across the membrane in the same direction as the ECDF (Fig. 1B). Thus X will carry current, Ix, across the membrane in accordance with a modified version of Ohms law

Ix = gx(Vm - Ex) where g, is the membrane conductance for ion X. In the steady state, when the cell is not signaling (i.e., at resting Vm), the concentration gradients of ions that are not in electrochemical equilibrium and that, therefore, exhibit net passive flux across the membrane, are maintained by active transport. Thus the passive flux of an ion in one direction will be offset by active transport in the opposite direction. The end result for all ions is no net movement of charge across the membrane and a stable, resting Vm. The deflection of Vm from rest is the basis of bioelectrical signal generation. This is accomplished by changing membrane conductance to an ion (or ions) that is (are) out of electrochemical equilibrium, resulting in a net membrane current and, therefore, a change in Vm. The membrane conductance for specific ions is altered by opening or closing specific gated ion channels. A change in membrane conductance for any ion X, which is not in electrochemical equilibrium, will cause a change in Ix

Ix =gx(Vm - Ex) Thus the balance between active and passive fluxes will be transiently disrupted, a net movement of charge across be transiently disrupted, a net movement of charge across the membrane will occur, Vm will deflect from its resting value, and a bioelectrical signal will be generated. For any given change in g, the direction of the resulting change in 1x and its magnitude, i.e., the nature of the signal, will be determined by the direction and magnitude of the electrochemical driving force acting on X.

FIG. 1. A: example of a neuron where electrical and chemical driving forces (EDF and CDF, respectively) acting on cation X are equal and in opposite directions, resulting in no net, or electrochemical, driving force (DF) for X, i.e., electrochemical equilibrium with respect to X. B: example of a neuron where outward CDF for cation X exceeds inward EDF, resulting in outward net driving force acting on X. Vm, membrane potential; [x+]i, [x+]e,, intra- and extracellular concentrations of cation X, respectively. g: mS/cm2 I: mA/cm2 Vm: -40 EK: -58 Ena: +50 Delta: 18 mV Delta: -110