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Endocrinology. 2014 Jan;155(1):98-107. doi: 10.1210/en.2013-1691. Epub 2013 Dec 20.

Role of calcium and EPAC in norepinephrine-induced ghrelin secretion.

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  • 1Division 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; 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; and Departments of Psychiatry (B.K.M., J.-C.C., I.S., A.K.W., A.K., S.O.-L., J.M.Z.) and Physiology (L.K., J.J.R.), University of Texas Southwestern Medical Center, Dallas, Texas 75390.


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 β1-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 Ca(2+) and cAMP. Several voltage-gated Ca(2+) 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 Ca(2+) levels both in the presence and absence of extracellular Ca(2+). Ca(2+)-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 Ca(2+) influx through L-type VGCCs and that NE stimulates ghrelin secretion predominantly through release of intracellular Ca(2+). Furthermore, cAMP and its downstream activation of EPAC are required for the normal ghrelin secretory response to NE.

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