Hypothesis & Theory: Effects of extracellular metabolic acidosis on the homeostasis of intracellular pH in hippocampal neurons

Patrice G Bouyer ^1* Sara Taki ² Fraser J. Moss ² Walter F. Boron ^2*

• ¹ Valparaiso University, Valparaiso, United States
• ² Case Western Reserve University, Cleveland, Ohio, United States

This Hypothesis & Theory contribution accompanies the research paper by Bouyer et al (Frontiers in Physiology xxx), the first to employ out-of-equilibrium (OOE) CO2/HCO3− solutions to examine systematically the intracellular-pH (pHi) effects of extracellular (o) metabolic acidosis (MAc) and its component parts: an isolated decrease in pHo (pure acidosis, pAc), and an isolated decrease in [HCO3−]o (pure metabolic/down, pMet). Here, after reviewing various kinds of acid-base disturbances and the use of OOE solutions, we discuss pHi “state” (the pHi in response to a single acid-base challenge) and “behavior” (the pHi transition observed between two successive challenges) and approaches for quantitating state and behavior. We then discuss the molecular basis for how individual extracellular acid-base disturbances influence pHi via effects on—and interactions among—acid-base transporters, acid-base sensors, and cellular constitution. Next, we examine the determinants of states and behaviors, their impact on the buffering of extracellular acid loads, and how variability in state and behavior might arise. We conclude with a consideration of how mathematical models—with their inherent limitations—might assist in the interpretation of experiments and qualitative models presented here. Among the themes that emerge are: (1) hippocampal neurons must have distinct sensors for pHo and [HCO3−]o; (2) these pHo- and [HCO3−]o-driven signal-transduction pathways produce additive pHi effects in naïve neurons (those not previously challenged by an acid-base disturbance); but (3) produce highly non-additive pHi effects in neurons previously challenged by MAc.