{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T04:15:59Z","timestamp":1747196159090,"version":"3.40.5"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"sep-conacyt","award":["CB-2011-01-167109"],"award-info":[{"award-number":["CB-2011-01-167109"]}]},{"name":"sep-conacyt","award":["CB-2013-01-220742"],"award-info":[{"award-number":["CB-2013-01-220742"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Inhibitory regulation of the heart is determined by both cholinergic M<jats:sub>2<\/jats:sub> receptors (M<jats:sub>2<\/jats:sub>R) and adenosine A<jats:sub>1<\/jats:sub> receptors (A<jats:sub>1<\/jats:sub>R) that activate the same signaling pathway, the ACh-gated inward rectifier K<jats:sup>+<\/jats:sup> (K<jats:sub>ACh<\/jats:sub>) channels via G<jats:sub>i\/o<\/jats:sub> proteins. Previously, we have shown that the agonist-specific voltage sensitivity of M<jats:sub>2<\/jats:sub>R underlies several voltage-dependent features of <jats:italic>I<\/jats:italic><jats:sub>KACh<\/jats:sub>, including the \u2018relaxation\u2019 property, which is characterized by a gradual increase or decrease of the current when cardiomyocytes are stepped to hyperpolarized or depolarized voltages, respectively. However, it is unknown whether membrane potential also affects A<jats:sub>1<\/jats:sub>R and how this could impact <jats:italic>I<\/jats:italic><jats:sub>KACh<\/jats:sub>. Upon recording whole-cell currents of guinea-pig cardiomyocytes, we found that stimulation of the A<jats:sub>1<\/jats:sub>R-G<jats:sub>i\/o<\/jats:sub>-<jats:italic>I<\/jats:italic><jats:sub>KACh<\/jats:sub> pathway with adenosine only caused a very slight voltage dependence in concentration-response relationships (~1.2-fold EC<jats:sub>50<\/jats:sub> increase with depolarization) that was not manifested in the relative affinity, as estimated by the current deactivation kinetics (\u03c4 = 4074 \u00b1 214 ms at -100 mV and \u03c4 = 4331 \u00b1 341 ms at +30 mV; <jats:italic>P<\/jats:italic> = 0.31). Moreover, <jats:italic>I<\/jats:italic><jats:sub>KACh<\/jats:sub> did not exhibit relaxation. Contrarily, activation of the M<jats:sub>2<\/jats:sub>R-G<jats:sub>i\/o<\/jats:sub>-<jats:italic>I<\/jats:italic><jats:sub>KACh<\/jats:sub> pathway with acetylcholine induced the typical relaxation of the current, which correlated with the clear voltage-dependent effect observed in the concentration-response curves (~2.8-fold EC<jats:sub>50<\/jats:sub> increase with depolarization) and in the <jats:italic>I<\/jats:italic><jats:sub>KACh<\/jats:sub> deactivation kinetics (\u03c4 = 1762 \u00b1 119 ms at -100 mV and \u03c4 = 1503 \u00b1 160 ms at +30 mV; <jats:italic>P<\/jats:italic> = 0.01). Our findings further substantiate the hypothesis of the agonist-specific voltage dependence of GPCRs and that the <jats:italic>I<\/jats:italic><jats:sub>KACh<\/jats:sub> relaxation is consequence of this property.<\/jats:p>","DOI":"10.1371\/journal.pone.0261960","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T21:04:40Z","timestamp":1642194280000},"page":"e0261960","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine"],"prefix":"10.1371","volume":"17","author":[{"given":"Ana Laura","family":"L\u00f3pez-Serrano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Zamora-C\u00e1rdenas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iv\u00e1n 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