A quantitative analysis of cell volume and resting potential determination and regulation in excitable cells

摘要

This paper quantifies recent experimental results through a general physical description of the mechanisms that might control two fundamental cellular parameters, resting potential (Em) and cell volume (Vc), thereby clarifying the complex relationships between them. Em was determined directly from a charge difference (CD) equation involving total intracellular ionic charge and membrane capacitance (Cm). This avoided the equilibrium condition dEm/dt = 0 required in determinations of Em by previous work based on the Goldman-Hodgkin-Katz equation and its derivatives and thus permitted precise calculation of Em even under non-equilibrium conditions. It could accurately model the influence upon Em of changes in Cm or Vc and of membrane transport processes such as the Na⁺–K⁺-ATPase and ion cotransport. Given a stable and adequate membrane Na⁺–K⁺-ATPase density (N), Vc and Em both converged to unique steady-state values even from sharply divergent initial intracellular ionic concentrations. For any constant set of transmembrane ion permeabilities, this set point of Vc was then determined by the intracellular membrane-impermeant solute content (X⁻i) and its mean charge valency (zX), while in contrast, the set point of Em was determined solely by z_X. Independent changes in membrane Na⁺ (P_Na) or K⁺ permeabilities (P_K) or activation of cation–chloride cotransporters could perturb V_c and E_m but subsequent reversal of such changes permitted full recovery of both V_c and E_m to the original set points. Proportionate changes in P_Na, P_K and N, or changes in Cl⁻ permeability (P_Cl) instead conserved steady-state V_c and E_m but altered their rates of relaxation following any discrete perturbation. P_Cl additionally determined the relative effect of cotransporter activity on V_c and E_m, in agreement with recent experimental results. In contrast, changes in X_i⁻ produced by introduction of a finite permeability term to X⁻ (P_X) that did not alter z_X caused sustained changes in V_c that were independent of E_m and that persisted when P_X returned to zero. Where such fluxes also altered the effective z_X they additionally altered the steady state E_m. This offers a basis for the suggested roles of amino acid fluxes in long-term volume regulatory processes in a variety of excitable tissues.