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While its signalling is assumed to be mediated via increases in cAMP, this study focused on elucidating the actual intracellular signalling pathways involved in CGRP\u2010induced relaxation of human isolated coronary arteries (HCA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>HCA were obtained from heart valve donors (27\u2009M, 25\u2009F, age 54\u2009\u00b1\u00a02\u00a0years). Concentration\u2013response curves to human \u03b1\u2010CGRP or forskolin were constructed in HCA segments, incubated with different inhibitors of intracellular signalling pathways, and intracellular cAMP levels were measured with and without stimulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Adenylyl cyclase (AC) inhibitors SQ22536\u2009+\u2009DDA and MDL\u201012330A, and PKA inhibitors Rp\u20108\u2010Br\u2010cAMPs and H89, did not inhibit CGRP\u2010induced relaxation of HCA, nor did the guanylyl cyclase inhibitor ODQ, PKG inhibitor KT5823, EPAC1\/2 inhibitor ESI09, potassium channel blockers TRAM\u201034\u2009+\u2009apamin, iberiotoxin or glibenclamide, or the G\u03b1<jats:sub>q<\/jats:sub> inhibitor YM\u2010254890. Phosphodiesterase inhibitors induced a concentration\u2010dependent decrease in the response to KCl but did not potentiate relaxation to CGRP. Relaxation to forskolin was not blocked by PKA or AC inhibitors, although AC inhibitors significantly inhibited the increase in cAMP. Inhibition of G\u03b2\u03b3 subunits using gallein significantly inhibited the relaxation to CGRP in human coronary arteries.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>While CGRP signalling is generally assumed to act via cAMP, the CGRP\u2010induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of G\u03b2\u03b3 subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP\u2010induced relaxation than generally believed.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16372","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T01:05:15Z","timestamp":1712538315000},"page":"2478-2491","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Intracellular pathways of calcitonin gene\u2010related peptide\u2010induced relaxation of human coronary arteries: A key role for G\u03b2\u03b3 subunit instead of cAMP"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5078-6764","authenticated-orcid":false,"given":"Tessa","family":"de Vries","sequence":"first","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sieneke","family":"Labruijere","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Rivera\u2010Mancilla","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.","family":"Garrelds","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"de Vries","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Schutter","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoon","family":"van den Bogaerdt","sequence":"additional","affiliation":[{"name":"Heart Valve Department ETB\u2010BISLIFE  Beverwijk The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Poyner","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences Aston University, Aston Triangle  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Ladds","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-3585","authenticated-orcid":false,"given":"A. 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