Role of calcium and EPAC in norepinephrine-induced ghrelin secretion

Bharath K. Mani, Jen Chieh Chuang, Lilja Kjalarsdottir, Ichiro Sakata, Angela K. Walker, Anna Kuperman, Sherri Osborne-Lawrence, Joyce J. Repa, Jeffrey M. Zigman

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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 to1-Adrenergic receptors on ghrelin cells. Here,weuseanimmortalized 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.NEinduced 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-inducedghrelin secretion,whereasanEPACagonistenhancedbasal ghrelin secretion.Weconclude 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.

Original languageEnglish (US)
Pages (from-to)98-107
Number of pages10
JournalEndocrinology
Volume155
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Endocrinology

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    Mani, B. K., Chuang, J. C., Kjalarsdottir, L., Sakata, I., Walker, A. K., Kuperman, A., Osborne-Lawrence, S., Repa, J. J., & Zigman, J. M. (2014). Role of calcium and EPAC in norepinephrine-induced ghrelin secretion. Endocrinology, 155(1), 98-107. https://doi.org/10.1210/en.2013-1691