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Adenosine A3 receptors (A3R) could counteract excessive A2AR activation, but their functional role in the atrium remains elusive, and we therefore aimed to address the impact of A3Rs on intracellular calcium homeostasis. For this purpose, we analyzed right atrial samples or myocytes from 53 patients without AF, using quantitative PCR, patch-clamp technique, immunofluorescent labeling or confocal calcium imaging. A3R mRNA accounted for 9% and A2AR mRNA for 32%. At baseline, A3R inhibition increased the transient inward current (ITI) frequency from 0.28 to 0.81 events\/min (p &lt; 0.05). Simultaneous stimulation of A2ARs and A3Rs increased the calcium spark frequency seven-fold (p &lt; 0.001) and the ITI frequency from 0.14 to 0.64 events\/min (p &lt; 0.05). Subsequent A3R inhibition caused a strong additional increase in the ITI frequency (to 2.04 events\/min; p &lt; 0.01) and increased phosphorylation at s2808 1.7-fold (p &lt; 0.001). These pharmacological treatments had no significant effects on L-type calcium current density or sarcoplasmic reticulum calcium load. In conclusion, A3Rs are expressed and blunt spontaneous calcium release at baseline and upon A2AR-stimulation in human atrial myocytes, pointing to A3R activation as a means to attenuate physiological and pathological elevations of spontaneous calcium release events.<\/jats:p>","DOI":"10.3390\/ijms24054404","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T03:25:56Z","timestamp":1677122756000},"page":"4404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Expression and Impact of Adenosine A3 Receptors on Calcium Homeostasis in Human Right Atrium"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8954-6058","authenticated-orcid":false,"given":"Carmen","family":"Tarifa","sequence":"first","affiliation":[{"name":"Biomedical Research Institute of Barcelona, IIBB-CSIC, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB Sant Pau), 08025 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7720-988X","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Jim\u00e9nez-S\u00e1bado","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB Sant Pau), 08025 Barcelona, Spain"},{"name":"Cardiology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Franco","sequence":"additional","affiliation":[{"name":"Departament de Bioqu\u00edmica i Biomedicina Molecular, Facultat de Biolog\u00eda, Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Montiel","sequence":"additional","affiliation":[{"name":"Cardiac Surgery Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Guerra","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB Sant Pau), 08025 Barcelona, Spain"},{"name":"Cardiology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0832-3739","authenticated-orcid":false,"given":"Francisco","family":"Ciruela","sequence":"additional","affiliation":[{"name":"Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L\u2019Hospitalet de Llobregat, Spain"},{"name":"Neuropharmacology & Pain Group, Neuroscience Program, Institut d\u2019Investigaci\u00f3 Biom\u00e8dica de Bellvitge, IDIBELL, 08907 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5493-3998","authenticated-orcid":false,"given":"Leif","family":"Hove-Madsen","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute of Barcelona, IIBB-CSIC, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigaci\u00f3 Biom\u00e8dica Sant Pau (IIB Sant Pau), 08025 Barcelona, Spain"},{"name":"Cardiology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1161\/01.CIR.0000162461.67140.4C","article-title":"Defective Cardiac Ryanodine Receptor Regulation during Atrial Fibrillation","volume":"111","author":"Vest","year":"2005","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"H812","DOI":"10.1152\/ajpheart.1994.267.2.H812","article-title":"Protein Kinase Inhibitors Reduce SR Ca Transport in Permeabilized Cardiac Myocytes","volume":"267","author":"Mattiazzi","year":"1994","journal-title":"Am. 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