Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

Maja S. Engelstoft; Won mee Park; Ichiro Sakata; Line V. Kristensen; Anna Sofie Husted; Sherri Osborne-Lawrence; Paul K. Piper; Angela K. Walker; Maria H. Pedersen; Mark K. Nøhr; Jie Pan; Christopher J. Sinz; Paul E. Carrington; Taro E. Akiyama; Robert M. Jones; Cong Tang; Kashan Ahmed; Stefan Offermanns; Kristoffer L. Egerod; Jeffrey M. Zigman; Thue W. Schwartz

doi:10.1016/j.molmet.2013.08.006

Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

Maja S. Engelstoft, Won mee Park, Ichiro Sakata, Line V. Kristensen, Anna Sofie Husted, Sherri Osborne-Lawrence, Paul K. Piper, Angela K. Walker, Maria H. Pedersen, Mark K. Nøhr, Jie Pan, Christopher J. Sinz, Paul E. Carrington, Taro E. Akiyama, Robert M. Jones, Cong Tang, Kashan Ahmed, Stefan Offermanns, Kristoffer L. Egerod, Jeffrey M. ZigmanThue W. Schwartz

Research output: Contribution to journal › Article › peer-review

254 Scopus citations

Abstract

The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.

Original language	English (US)
Pages (from-to)	376-392
Number of pages	17
Journal	Molecular Metabolism
Volume	2
Issue number	4
DOIs	https://doi.org/10.1016/j.molmet.2013.08.006
State	Published - Nov 2013

Keywords

Enteroendocrine
G protein signaling
GPCR
Ghrelin
Metabolites
Secretion

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molmet.2013.08.006

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Engelstoft, M. S., Park, W. M., Sakata, I., Kristensen, L. V., Husted, A. S., Osborne-Lawrence, S., Piper, P. K., Walker, A. K., Pedersen, M. H., Nøhr, M. K., Pan, J., Sinz, C. J., Carrington, P. E., Akiyama, T. E., Jones, R. M., Tang, C., Ahmed, K., Offermanns, S., Egerod, K. L., ... Schwartz, T. W. (2013). Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Molecular Metabolism, 2(4), 376-392. https://doi.org/10.1016/j.molmet.2013.08.006

Engelstoft, MS, Park, WM, Sakata, I, Kristensen, LV, Husted, AS, Osborne-Lawrence, S, Piper, PK, Walker, AK, Pedersen, MH, Nøhr, MK, Pan, J, Sinz, CJ, Carrington, PE, Akiyama, TE, Jones, RM, Tang, C, Ahmed, K, Offermanns, S, Egerod, KL, Zigman, JM & Schwartz, TW 2013, 'Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells', Molecular Metabolism, vol. 2, no. 4, pp. 376-392. https://doi.org/10.1016/j.molmet.2013.08.006

@article{0e06e3e921e84a15a59f6877c1e8d869,

title = "Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells",

abstract = "The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.",

keywords = "Enteroendocrine, G protein signaling, GPCR, Ghrelin, Metabolites, Secretion",

author = "Engelstoft, {Maja S.} and Park, {Won mee} and Ichiro Sakata and Kristensen, {Line V.} and Husted, {Anna Sofie} and Sherri Osborne-Lawrence and Piper, {Paul K.} and Walker, {Angela K.} and Pedersen, {Maria H.} and N{\o}hr, {Mark K.} and Jie Pan and Sinz, {Christopher J.} and Carrington, {Paul E.} and Akiyama, {Taro E.} and Jones, {Robert M.} and Cong Tang and Kashan Ahmed and Stefan Offermanns and Egerod, {Kristoffer L.} and Zigman, {Jeffrey M.} and Schwartz, {Thue W.}",

note = "Funding Information: We are grateful for the expert technical assistance from Susanne Hummelgaard. The Novo Nordisk Foundation Center for Basic Metabolic Research ( http://www.metabol.ku.dk ) is supported by an unconditional grant from the Novo Nordisk Foundation to University of Copenhagen . The project was also supported by the UNIK project for Food, Fitness & Pharma ( http://www.foodfitnesspharma.ku.dk ) from the Danish Ministry of Science, Technology and Innovation . T.W.S and K.L.E were further supported by grants from the Lundbeck Foundation and from the Danish Medical Research Council . M.S.E was supported by a PhD scholarship from the Faculty of Health and Medical Sciences, University of Copenhagen . P.K.P. received funding from the Endocrine Fellows Foundation . A.K.W. was supported by NIH ( T32DA7290 ). K.A. was supported by an EMBO long-term fellowship . ",

year = "2013",

month = nov,

doi = "10.1016/j.molmet.2013.08.006",

language = "English (US)",

volume = "2",

pages = "376--392",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier GmbH",

number = "4",

}

TY - JOUR

T1 - Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

AU - Engelstoft, Maja S.

AU - Park, Won mee

AU - Sakata, Ichiro

AU - Kristensen, Line V.

AU - Husted, Anna Sofie

AU - Osborne-Lawrence, Sherri

AU - Piper, Paul K.

AU - Walker, Angela K.

AU - Pedersen, Maria H.

AU - Nøhr, Mark K.

AU - Pan, Jie

AU - Sinz, Christopher J.

AU - Carrington, Paul E.

AU - Akiyama, Taro E.

AU - Jones, Robert M.

AU - Tang, Cong

AU - Ahmed, Kashan

AU - Offermanns, Stefan

AU - Egerod, Kristoffer L.

AU - Zigman, Jeffrey M.

AU - Schwartz, Thue W.

N1 - Funding Information: We are grateful for the expert technical assistance from Susanne Hummelgaard. The Novo Nordisk Foundation Center for Basic Metabolic Research ( http://www.metabol.ku.dk ) is supported by an unconditional grant from the Novo Nordisk Foundation to University of Copenhagen . The project was also supported by the UNIK project for Food, Fitness & Pharma ( http://www.foodfitnesspharma.ku.dk ) from the Danish Ministry of Science, Technology and Innovation . T.W.S and K.L.E were further supported by grants from the Lundbeck Foundation and from the Danish Medical Research Council . M.S.E was supported by a PhD scholarship from the Faculty of Health and Medical Sciences, University of Copenhagen . P.K.P. received funding from the Endocrine Fellows Foundation . A.K.W. was supported by NIH ( T32DA7290 ). K.A. was supported by an EMBO long-term fellowship .

PY - 2013/11

Y1 - 2013/11

N2 - The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.

AB - The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.

KW - Enteroendocrine

KW - G protein signaling

KW - GPCR

KW - Ghrelin

KW - Metabolites

KW - Secretion

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U2 - 10.1016/j.molmet.2013.08.006

DO - 10.1016/j.molmet.2013.08.006

M3 - Article

C2 - 24327954

AN - SCOPUS:84889093491

SN - 2212-8778

VL - 2

SP - 376

EP - 392

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 4

ER -

Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

Abstract

Keywords

ASJC Scopus subject areas

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