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HYPOTHESIS AND THEORY article

Front. Physiol.
Sec. Membrane Physiology and Membrane Biophysics
Volume 15 - 2024 | doi: 10.3389/fphys.2024.1494956
This article is part of the Research Topic Advances in Acid-Base Physiology: From Single Transporters to Physiology View all 6 articles

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

Provisionally accepted
Patrice G Bouyer Patrice G Bouyer 1*Sara Taki Sara Taki 2Fraser J. Moss Fraser J. Moss 2Walter F. Boron Walter F. Boron 2*
  • 1 Valparaiso University, Valparaiso, United States
  • 2 Case Western Reserve University, Cleveland, Ohio, United States

The final, formatted version of the article will be published soon.

    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.

    Keywords: CO2/HCO - 3 out of equilibrium solutions, pH regulation, pHo sensor, HCO3 sensor, Neurons

    Received: 11 Sep 2024; Accepted: 27 Nov 2024.

    Copyright: © 2024 Bouyer, Taki, Moss and Boron. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Patrice G Bouyer, Valparaiso University, Valparaiso, United States
    Walter F. Boron, Case Western Reserve University, Cleveland, 44106, Ohio, United States

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