{"doi":"10.1113/jp282126","title":"The HVCN1 voltage‐gated proton channel contributes to pH regulation in canine ventricular myocytes","abstract":"Abstract 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.","journal":"The Journal of Physiology","year":2022,"id":253257,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":898700,"name":"Xiaoqian Gao","orcid":"0009-0002-3565-1412","position":1,"is_corresponding":false},{"id":297841,"name":"Yutian Li","orcid":"0000-0002-5118-0916","position":2,"is_corresponding":false},{"id":420774,"name":"Thomas E. DeCoursey","orcid":"0000-0002-4263-180X","position":3,"is_corresponding":false},{"id":701291,"name":"Gary E. Shull","orcid":null,"position":4,"is_corresponding":false},{"id":898701,"name":"Hong‐Sheng Wang","orcid":"0000-0001-7654-6016","position":5,"is_corresponding":false},{"id":708879,"name":"Jianyong Ma","orcid":"0000-0003-1145-7121","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T00:24:55.325369Z","pmid":"35244217","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}