{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:41:50Z","timestamp":1791319310337,"version":"4.3.1"},"reference-count":51,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,1]]},"abstract":"<jats:p>Ghrelin is an orexigenic hormone secreted principally from a distinct population of gastric endocrine cells. Molecular mechanisms regulating ghrelin secretion are mostly unknown. Recently, norepinephrine (NE) was shown to enhance ghrelin release by binding to \u03b21-adrenergic receptors on ghrelin cells. Here, we use an immortalized stomach-derived ghrelin cell line to further characterize the intracellular signaling pathways involved in NE-induced ghrelin secretion, with a focus on the roles of Ca2+ and cAMP. Several voltage-gated Ca2+ channel (VGCC) family members were found by quantitative PCR to be expressed by ghrelin cells. Nifedipine, a selective L-type VGCC blocker, suppressed both basal and NE-stimulated ghrelin secretion. NE induced elevation of cytosolic Ca2+ levels both in the presence and absence of extracellular Ca2+. Ca2+-sensing synaptotagmins Syt7 and Syt9 were also highly expressed in ghrelin cell lines, suggesting that they too help mediate ghrelin secretion. Raising cAMP with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also stimulated ghrelin secretion, although such a cAMP-mediated effect likely does not involve protein kinase A, given the absence of a modulatory response to a highly selective protein kinase A inhibitor. However, pharmacological inhibition of another target of cAMP, exchange protein-activated by cAMP (EPAC), did attenuate both basal and NE-induced ghrelin secretion, whereas an EPAC agonist enhanced basal ghrelin secretion. We conclude that constitutive ghrelin secretion is primarily regulated by Ca2+ influx through L-type VGCCs and that NE stimulates ghrelin secretion predominantly through release of intracellular Ca2+. Furthermore, cAMP and its downstream activation of EPAC are required for the normal ghrelin secretory response to NE.<\/jats:p>","DOI":"10.1210\/en.2013-1691","type":"journal-article","created":{"date-parts":[[2013,11,5]],"date-time":"2013-11-05T04:13:53Z","timestamp":1383624833000},"page":"98-107","source":"Crossref","is-referenced-by-count":24,"title":["Role of Calcium and EPAC in Norepinephrine-Induced Ghrelin Secretion"],"prefix":"10.1210","volume":"155","author":[{"given":"Bharath K.","family":"Mani","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism (B.K.M., J.-C.C., I.S., A.K.W., A.K., S.O.-L., J.M.Z.), Department of Internal Medicine"},{"name":"Division of Hypothalamic research (B.K.M., J.-C.C., L.K., I.S., A.K.W., A.K., S.O.-L., J.J.R., J.M.Z.), Department of Internal Medicine"},{"name":"Departments of Psychiatry (B.K.M., J.-C.C., I.S., A.K.W., A.K., S.O.-L., J.M.Z.), University of Texas Southwestern Medical Center, Dallas, Texas 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