Acidic environments trigger intracellular H+-sensing FAK proteins to re-balance sarcolemmal acid–base transporters and auto-regulate cardiomyocyte pH

Author:

Wilson Abigail D1ORCID,Richards Mark A1,Curtis M Kate1ORCID,Gunadasa-Rohling Mala1,Monterisi Stefania1,Loonat Aminah A1,Miller Jack J123ORCID,Ball Vicky1ORCID,Lewis Andrew3ORCID,Tyler Damian J13ORCID,Moshnikova Anna4,Andreev Oleg A4,Reshetnyak Yana K4,Carr Carolyn1ORCID,Swietach Pawel1ORCID

Affiliation:

1. Department of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK

2. Department of Physics, Clarendon Laboratory, University of Oxford, Parks Road, Oxford OX1 3PU, UK

3. Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Radcliffe Department of Medicine, Level 0, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK

4. Physics Department, University of Rhode Island, 2 Lippitt Rd, Kingston, RI 02881, USA

Abstract

Abstract Aims In cardiomyocytes, acute disturbances to intracellular pH (pHi) are promptly corrected by a system of finely tuned sarcolemmal acid–base transporters. However, these fluxes become thermodynamically re-balanced in acidic environments, which inadvertently causes their set-point pHi to fall outside the physiological range. It is unclear whether an adaptive mechanism exists to correct this thermodynamic challenge, and return pHi to normal. Methods and results Following left ventricle cryo-damage, a diffuse pattern of low extracellular pH (pHe) was detected by acid-sensing pHLIP. Despite this, pHi measured in the beating heart (13C NMR) was normal. Myocytes had adapted to their acidic environment by reducing Cl−/HCO3− exchange (CBE)-dependent acid-loading and increasing Na+/H+ exchange (NHE1)-dependent acid-extrusion, as measured by fluorescence (cSNARF1). The outcome of this adaptation on pHi is revealed as a cytoplasmic alkalinization when cells are superfused at physiological pHe. Conversely, mice given oral bicarbonate (to improve systemic buffering) had reduced myocardial NHE1 expression, consistent with a needs-dependent expression of pHi-regulatory transporters. The response to sustained acidity could be replicated in vitro using neonatal ventricular myocytes incubated at low pHe for 48 h. The adaptive increase in NHE1 and decrease in CBE activities was linked to Slc9a1 (NHE1) up-regulation and Slc4a2 (AE2) down-regulation. This response was triggered by intracellular H+ ions because it persisted in the absence of CO2/HCO3− and became ablated when acidic incubation media had lower chloride, a solution manoeuvre that reduces the extent of pHi-decrease. Pharmacological inhibition of FAK-family non-receptor kinases, previously characterized as pH-sensors, ablated this pHi autoregulation. In support of a pHi-sensing role, FAK protein Pyk2 (auto)phosphorylation was reduced within minutes of exposure to acidity, ahead of adaptive changes to pHi control. Conclusions Cardiomyocytes fine-tune the expression of pHi-regulators so that pHi is at least 7.0. This autoregulatory feedback mechanism defines physiological pHi and protects it during pHe vulnerabilities.

Funder

British Heart Foundation Programme

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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