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Although not well understood this allows normally contractile VSMCs to become proliferative following vessel injury, a process essential for repair but which also contributes to vascular remodelling, atherogenesis and restenosis. Here we show that the Ca<jats:sup>2+<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>-sensitive enzyme, soluble adenylyl cyclase (sAC), links Ca<jats:sup>2+<\/jats:sup> influx in human coronary artery smooth muscle cells (hCASMCs) to 3\u2032,5\u2032-cyclic adenosine monophosphate (cAMP) generation and phosphorylation of the transcription factor Ca<jats:sup>2+<\/jats:sup>\/cAMP response element binding protein (CREB). Store-operated Ca<jats:sup>2+<\/jats:sup> entry (SOCE) into hCASMCs expressing the FRET-based cAMP biosensor H187 induced a rise in cAMP that mirrored cytosolic [Ca<jats:sup>2+<\/jats:sup>]. SOCE also activated the cAMP effector, protein kinase A (PKA), as determined by the PKA reporter, AKAR4-NES, and induced phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and CREB. Transmembrane adenylyl cyclase inhibition had no effect on the SOCE-induced rise in cAMP, while sAC inhibition abolished SOCE-generated cAMP and significantly reduced SOCE-induced VASP and CREB phosphorylation. This suggests that SOCE in hCASMCs activates sAC which in turn activates the cAMP\/PKA\/CREB axis. sAC, which is insensitive to G-protein modulation but responsive to Ca<jats:sup>2+<\/jats:sup>, pH and ATP, may therefore act as an overlooked regulatory node in vascular Ca<jats:sup>2+<\/jats:sup>-transcription coupling.<\/jats:p>","DOI":"10.1038\/s41598-019-43821-3","type":"journal-article","created":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T22:03:33Z","timestamp":1557785013000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Soluble adenylyl cyclase links Ca2+ entry to Ca2+\/cAMP-response element binding protein (CREB) activation in vascular smooth muscle"],"prefix":"10.1038","volume":"9","author":[{"given":"Tony","family":"Parker","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai-Wen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Declan","family":"Manning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Dart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,5,13]]},"reference":[{"key":"43821_CR1","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/S0008-6363(01)00444-8","volume":"53","author":"TD Izzard","year":"2002","unstructured":"Izzard, T. 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