Identification of GPR83 as the receptor for the neuroendocrine peptide PEN.
PEN is an abundant peptide in the brain that has been implicated in the regulation of feeding. We identified a receptor for PEN in mouse hypothalamus and Neuro2A cells. PEN bound to and activated GPR83, a G protein (heterotrimeric guanine nucleotide)-binding protein)-coupled receptor (GPCR). Reduction of GPR83 expression in mouse brain and Neuro2A cells reduced PEN binding and signaling, consistent with GPR83 functioning as the major receptor for PEN. In some brain regions, GPR83 colocalized with GPR171, a GPCR that binds the neuropeptide bigLEN, another neuropeptide that is involved in feeding and is generated from the same precursor protein as is PEN. Coexpression of these two receptors in cell lines altered the signaling properties of each receptor, suggesting a functional interaction. Our data established PEN as a neuropeptide that binds GPR83 and suggested that these two ligand-receptor systems-PEN-GPR83 and bigLEN-GPR171-may be functionally coupled in the regulation of feeding.
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Ivone
I
Gomes
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Erin N
EN
Bobeck
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Elyssa B
EB
Margolis
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Achla
A
Gupta
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Salvador
S
Sierra
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Amanda K
AK
Fakira
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Wakako
W
Fujita
Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany. Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
Timo D
TD
Müller
Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin, 13125 Berlin, Germany.
Anne
A
Müller
Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany. Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
Matthias H
MH
Tschöp
Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin, 13125 Berlin, Germany.
Gunnar
G
Kleinau
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Lloyd D
LD
Fricker
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. lakshmi.devi@mssm.edu.
Lakshmi A
LA
Devi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001069:Appetite Regulation / Q000502:physiology; D015153:Blotting, Western; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D009478:Neuropeptide Y / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
C584651:GPR171 protein, mouse; C501984:Gpr83 protein, mouse; D009478:Neuropeptide Y; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D000255:Adenosine Triphosphate