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 Lihme 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 Lihme Egerod, Jeffrey M ZigmanThue W Schwartz

192 Citations (Scopus)

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
Journal	Molecular Metabolism
Volume	2
Issue number	4
Pages (from-to)	376-92
Number of pages	17
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2013.08.006
Publication status	Published - Nov 2013

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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), 376-92. https://doi.org/10.1016/j.molmet.2013.08.006

Engelstoft, MS, Park, W-M, 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. 376-92. https://doi.org/10.1016/j.molmet.2013.08.006

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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.",

author = "Engelstoft, {Maja S} and Won-Mee Park 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 Lihme} and Zigman, {Jeffrey M} and Schwartz, {Thue W}",

year = "2013",

month = nov,

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

language = "English",

volume = "2",

pages = "376--92",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

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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 Lihme

AU - Zigman, Jeffrey M

AU - Schwartz, Thue W

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.

U2 - 10.1016/j.molmet.2013.08.006

DO - 10.1016/j.molmet.2013.08.006

M3 - Journal article

C2 - 24327954

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

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