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 Citations (Scopus)

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 2014

Fingerprint

Ghrelin
Norepinephrine
Calcium
Proteins
Cyclic AMP-Dependent Protein Kinases
Stomach
Synaptotagmins
1-Methyl-3-isobutylxanthine
Cell Line
Phosphodiesterase Inhibitors
Endocrine Cells
Nifedipine
Protein Kinase Inhibitors
Adrenergic Receptors

ASJC Scopus subject areas

  • Endocrinology

Cite this

Mani, B. K., Chuang, J. C., Kjalarsdottir, L., Sakata, I., Walker, A. K., Kuperman, A., ... 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

Role of calcium and EPAC in norepinephrine-induced ghrelin secretion. / Mani, Bharath K.; Chuang, Jen Chieh; Kjalarsdottir, Lilja; Sakata, Ichiro; Walker, Angela K.; Kuperman, Anna; Osborne-Lawrence, Sherri; Repa, Joyce J.; Zigman, Jeffrey M.

In: Endocrinology, Vol. 155, No. 1, 01.2014, p. 98-107.

Research output: Contribution to journalArticle

Mani, BK, Chuang, JC, Kjalarsdottir, L, Sakata, I, Walker, AK, Kuperman, A, Osborne-Lawrence, S, Repa, JJ & Zigman, JM 2014, 'Role of calcium and EPAC in norepinephrine-induced ghrelin secretion', Endocrinology, vol. 155, no. 1, pp. 98-107. https://doi.org/10.1210/en.2013-1691
Mani BK, Chuang JC, Kjalarsdottir L, Sakata I, Walker AK, Kuperman A et al. Role of calcium and EPAC in norepinephrine-induced ghrelin secretion. Endocrinology. 2014 Jan;155(1):98-107. https://doi.org/10.1210/en.2013-1691
Mani, Bharath K. ; Chuang, Jen Chieh ; Kjalarsdottir, Lilja ; Sakata, Ichiro ; Walker, Angela K. ; Kuperman, Anna ; Osborne-Lawrence, Sherri ; Repa, Joyce J. ; Zigman, Jeffrey M. / Role of calcium and EPAC in norepinephrine-induced ghrelin secretion. In: Endocrinology. 2014 ; Vol. 155, No. 1. pp. 98-107.
@article{7611fadba5594e1ea0483c69b3cd6492,
title = "Role of calcium and EPAC in norepinephrine-induced ghrelin secretion",
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.",
author = "Mani, {Bharath K.} and Chuang, {Jen Chieh} and Lilja Kjalarsdottir and Ichiro Sakata and Walker, {Angela K.} and Anna Kuperman and Sherri Osborne-Lawrence and Repa, {Joyce J.} and Zigman, {Jeffrey M.}",
year = "2014",
month = "1",
doi = "10.1210/en.2013-1691",
language = "English (US)",
volume = "155",
pages = "98--107",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "1",

}

TY - JOUR

T1 - Role of calcium and EPAC in norepinephrine-induced ghrelin secretion

AU - Mani, Bharath K.

AU - Chuang, Jen Chieh

AU - Kjalarsdottir, Lilja

AU - Sakata, Ichiro

AU - Walker, Angela K.

AU - Kuperman, Anna

AU - Osborne-Lawrence, Sherri

AU - Repa, Joyce J.

AU - Zigman, Jeffrey M.

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84891424484&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891424484&partnerID=8YFLogxK

U2 - 10.1210/en.2013-1691

DO - 10.1210/en.2013-1691

M3 - Article

VL - 155

SP - 98

EP - 107

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 1

ER -