{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T16:34:57Z","timestamp":1768408497451,"version":"3.49.0"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T00:00:00Z","timestamp":1576454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Fund for Scientific Research Flanders"},{"DOI":"10.13039\/501100004385","name":"Ghent University","doi-asserted-by":"publisher","award":["BOF 01IO8314"],"award-info":[{"award-number":["BOF 01IO8314"]}],"id":[{"id":"10.13039\/501100004385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Research Foundation Flanders","doi-asserted-by":"publisher","award":["1124418"],"award-info":[{"award-number":["1124418"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Connexin-based gap junctions are crucial for electrical communication in the heart; they are each composed of two docked hemichannels (HCs), supplied as unpaired channels via the sarcolemma. When open, an unpaired HC forms a large pore, high-conductance and Ca2+-permeable membrane shunt pathway that may disturb cardiomyocyte function. HCs composed of connexin 43 (Cx43), a major cardiac connexin, can be opened by electrical stimulation but only by very positive membrane potentials. Here, we investigated the activation of Cx43 HCs in murine ventricular cardiomyocytes voltage-clamped at \u221270 mV.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Using whole-cell patch-clamp, co-immunoprecipitation, western blot analysis, immunocytochemistry, proximity ligation assays, and protein docking studies, we found that stimulation of ryanodine receptors (RyRs) triggered unitary currents with a single-channel conductance of \u223c220 pS, which were strongly reduced by Cx43 knockdown. Recordings under Ca2+-clamp conditions showed that both RyR activation and intracellular Ca2+ elevation were necessary for HC opening. Proximity ligation studies indicated close Cx43-RyR2 apposition (&amp;lt;40 nm), and both proteins co-immunoprecipitated indicating physical interaction. Molecular modelling suggested a strongly conserved RyR-mimicking peptide sequence (RyRHCIp), which inhibited RyR\/Ca2+ HC activation but not voltage-triggered activation. The peptide also slowed down action potential repolarization. Interestingly, alterations in the concerned RyR sequence are known to be associated with primary familial hypertrophic cardiomyopathy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our results demonstrate that Cx43 HCs are intimately linked to RyRs, allowing them to open at negative diastolic membrane potential in response to RyR activation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvz340","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T04:30:12Z","timestamp":1576125012000},"page":"123-136","source":"Crossref","is-referenced-by-count":39,"title":["RyR2 regulates Cx43 hemichannel intracellular Ca2+-dependent activation in cardiomyocytes"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5931-3576","authenticated-orcid":false,"given":"Alessio","family":"Lissoni","sequence":"first","affiliation":[{"name":"Department of Basic and Applied Medical Sciences\u2014Physiology Group, Ghent University, Ghent 9000, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6692-2150","authenticated-orcid":false,"given":"Paco","family":"Hulpiau","sequence":"additional","affiliation":[{"name":"Department of Bio-Medical Sciences, HOWEST University of Applied Sciences (Hogeschool West-Vlaanderen), Bruges, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5798-3923","authenticated-orcid":false,"given":"T\u00e2nia","family":"Martins-Marques","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Medical Sciences\u2014Physiology Group, Ghent University, Ghent 9000, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5968-4828","authenticated-orcid":false,"given":"Geert","family":"Bultynck","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Laboratory of Molecular and Cellular Signaling, KU Leuven, Leuven, Belgium"}]},{"given":"Rainer","family":"Schulz","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Physiologie, JustusLiebig Universit\u00e4t Giessen, Giessen, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0960-683X","authenticated-orcid":false,"given":"Katja","family":"Witschas","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Medical Sciences\u2014Physiology Group, Ghent University, Ghent 9000, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5786-8447","authenticated-orcid":false,"given":"Henrique","family":"Girao","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1885-7606","authenticated-orcid":false,"given":"Maarten","family":"De Smet","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Medical Sciences\u2014Physiology Group, Ghent University, Ghent 9000, Belgium"}]},{"given":"Luc","family":"Leybaert","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Medical Sciences\u2014Physiology Group, Ghent University, Ghent 9000, Belgium"}]}],"member":"286","published-online":{"date-parts":[[2019,12,16]]},"reference":[{"key":"2021011510043272900_cvz340-B1","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.hrthm.2011.10.028","article-title":"Connexin43 and the regulation of intercalated disc function","volume":"9","author":"Delmar","year":"2012","journal-title":"Hear. 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