The HVCN1 voltage‐gated proton channel contributes to pH regulation in canine ventricular myocytes

Regulation of intracellular pH (pH i ) in cardiomyocytes is crucial for cardiac function; however, currently known mechanisms for direct or indirect extrusion of acid from cardiomyocytes seem insufficient for energetically efficient extrusion of the massive H + loads generated under in vivo conditions. In cardiomyocytes, voltage‐sensitive H + channel activity mediated by the HVCN1 proton channel would be a highly efficient means of disposing of H + , while avoiding Na + loading, as occurs during direct acid extrusion via Na + /H + exchange or indirect acid extrusion via Na + –HCO 3 − cotransport. PCR and immunoblotting demonstrated expression of HVCN1 mRNA and protein in canine heart. Patch clamp analysis of canine ventricular myocytes revealed a voltage‐gated H + current that was highly H + ‐selective. The current was blocked by external Zn 2+ and the HVCN1 blocker 5‐chloro‐2‐guanidinobenzimidazole. Both the gating and Zn 2+ blockade of the current were strongly influenced by the pH gradient across the membrane. All characteristics of the observed current were consistent with the known hallmarks of HVCN1‐mediated H + current. Inhibition of HVCN1 and the NHE1 Na + /H + exchanger, singly and in combination, showed that either mechanism is largely sufficient to maintain pH i in beating cardiomyocytes, but that inhibition of both activities causes rapid acidification. These results show that HVCN1 is expressed in canine ventricular myocytes and provides a major H + extrusion activity, with a capacity similar to that of NHE1. In the beating heart in vivo , this activity would allow Na + ‐independent extrusion of H + during each action potential and, when functionally coupled with anion transport mechanisms, could facilitate transport‐mediated CO 2 disposal. Key points Intracellular pH (pH i ) regulation is crucial for cardiac function, as acidification depresses contractility and causes arrhythmias. H + ions are generated in cardiomyocytes from metabolic processes and particularly from CO 2 hydration, which has been shown to facilitate CO 2 venting from mitochondria. Currently, the NHE1 Na + /H + exchanger is viewed as the dominant H + extrusion mechanism in cardiac muscle. We show that the HVCN1 voltage‐gated proton channel is present and functional in canine ventricular myocytes, and that HVCN1 and NHE1 both contribute to pH i regulation. HVCN1 provides an energetically efficient mechanism of H + extrusion that would not cause Na + loading, which can cause pathology, and that could contribute to transport‐mediated CO 2 disposal. These results provide a major advance in our understanding of pH i regulation in cardiac muscle.