title: Transcriptional and Functional Characterization of the G Protein-Coupled Receptor Repertoire of Gastric Somatostatin Cells.
abstract: In the stomach, somatostatin (SST) acts as a general paracrine negative regulator of exocrine secretion of gastric acid and pepsinogen and endocrine secretion of gastrin, ghrelin, and histamine. Using reporter mice expressing red fluorescent protein (RFP) under control of the SST promotor, we have characterized the G protein-coupled receptors expressed in gastric Sst-RFP-positive cells and probed their effects on SST secretion in primary cell cultures. Surprisingly, besides SST, amylin and PYY were also highly enriched in the SST cells. Several receptors found to regulate SST secretion were highly expressed and/or enriched. 1) The metabolite receptors calcium-sensing receptor and free fatty acid receptor 4 (GPR120) functioned as positive and negative regulators, respectively. 2) Among the neurotransmitter receptors, adrenergic receptors α1a, α2a, α2b, and β1 were all highly expressed, with norepinephrine and isoproterenol acting as positive regulators. The muscarinic receptor M3 acted as a positive regulator, whereas M4 was conceivably a negative regulator. 3) Of the hormone receptors, the GLP-1 and GIP receptors, CCKb (stimulated by both CCK and gastrin) and surprisingly the melanocortin MC1 receptor were all positive regulators. 4) The neuropeptide receptors for calcitonin gene-related peptide, adrenomedullin, and vasoactive intestinal peptide acted as positive regulators, no effect was observed using galanin and nociceptin although transcripts for the corresponding receptors appeared highly expressed. 5) The SST receptors 1 and 2 functioned in an autocrine negative feedback loop. Thus, the article provides a comprehensive map of receptors through which SST secretion is regulated by hormones, neurotransmitters, neuropeptides and metabolites that act directly on the SST cells in the gastric mucosa.
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Kristoffer L
authors.initials: KL
authors.lastname: Egerod
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Maja S
authors.initials: MS
authors.lastname: Engelstoft
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Mari L
authors.initials: ML
authors.lastname: Lund
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Kaare V
authors.initials: KV
authors.lastname: Grunddal
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Mirabella
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Dominique
authors.initials: D
authors.lastname: Barir-Jensen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Eva B
authors.initials: EB
authors.lastname: Nygaard
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Natalia
authors.initials: N
authors.lastname: Petersen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., J.J.H., T.W.S.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Laboratory for Molecular Pharmacology (K.L.E., M.S.E., M.L.L., K.V.G., M.Z., D.B.-J., E.B.N., N.P., T.W.S.), Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; and Department of Biomedical Sciences (J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D019894:Peptide YY / Q000235:genetics / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D019864:Somatostatin-Secreting Cells / Q000378:metabolism*; D013270:Stomach / Q000166:cytology; D059467:Transcriptome; D000097573:Red Fluorescent Protein
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D058228:Islet Amyloid Polypeptide; D008164:Luminescent Proteins; D019894:Peptide YY; D011941:Receptors, Adrenergic; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic; D018013:Receptors, Neuropeptide; D017481:Receptors, Somatostatin; D013004:Somatostatin; D000097573:Red Fluorescent Protein; C498007:FFAR4 protein, mouse