Intracellular pH Regulation

Abstract

Because of the vast number of cellular processes sensitive to changes in pH, the control of intracellular pH (pH_i) is of vital importance both for the individual cell and for the organism as a whole. The fundamental problem that pH_iregulating mechanisms must address is the chronic tendency toward intracellular acidification. Depending on the conditions of incubation, a chronic intracellular acid load can be imposed by cellular metabolism. However, a nearly universal source of chronic acid loading are the fluxes across the cell membrane of H⁺ and of ionized weak acids and bases. Consider a cell having a transmembrane voltage (V_m) of -60 mV (cell negative) and an extracellular pH (pH_o) of 7.4. The Nernst equation predicts that pH_i would be ∼ 6.4 if H⁺ were in electrochemical equilibrium across the cell membrane. Because the actual pH_i is nearly a full pH unit higher, there is a substantial gradient favoring the influx of H⁺, and one of equal magnitude favoring the efflux of OH⁻. It can be shown (see Section 4.1) that the anionic, conjugate weak base (e.g., HCO₃ ⁻ ) of any neutral weak acid (e.g., CO₂) is influenced by the same electrochemical gradient as that for OH⁻, provided the neutral weak acid is equilibrated across the cell membrane. Similarly, the electrochemical gradient for any cationic conjugate weak acid (e.g., NH₄ ⁺ ) of a neutral weak base (e.g., NH₃) is the same as that for H⁺, provided the neutral weak base is in equilibrium across the cell membrane. Thus, the passive fluxes of H⁺, and of ionized weak acids or bases will all produce a chronic intracellular acid load. The gradual fall of pH_i toward its equilibrium value (i.e., ∼ 6.4 in this example) can be forestalled only by an active-transport process that extrudes acid from the cell at a rate equal to the total rate of acid accumulation.