1521-0081/70/4/763–835$35.00 https://doi.org/10.1124/pr.117.015388 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:763–835, October 2018 Copyright © 2018 The Author(s). This is an open access article distributed under the CC BY Attribution 4.0 International license. ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature Thomas Günther, Giovanni Tulipano, Pascal Dournaud, Corinne Bousquet, Zsolt Csaba, Hans-Jürgen Kreienkamp, Amelie Lupp, Márta Korbonits, Justo P. Castaño, Hans-Jürgen Wester, Michael Culler,1 Shlomo Melmed, and Stefan Schulz Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P. C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.) Downloaded from Abstract ...................................................................................765 I. Introduction and Historical Perspective ....................................................765 II. Endogenous Ligands .......................................................................767 A. Somatostatin . ........................................................................767 1. Somatostatin Gene and Peptide Structure . ..........................................767 by guest on October 2, 2021 2. Regulation of Gene Expression and Peptide Release . ...............................768 3. Anatomic Framework . ............................................................768 4. Functions. ........................................................................768 B. Cortistatin .............................................................................769 III. Somatostatin Receptors . ..................................................................770 A. Nomenclature. ........................................................................770 B. General Properties . ..................................................................771 IV. Somatostatin Receptor 1 . ..................................................................773 A. Somatostatin Receptor 1 Structure......................................................773 B. Somatostatin Receptor 1 Signaling Mechanisms . .....................................773 C. Somatostatin Receptor 1 Regulation and Trafficking ....................................775 D. Somatostatin Receptor 1 Interacting Proteins. ..........................................776 E. Somatostatin Receptor 1 Anatomic Framework .........................................776 Address correspondence to: Dr. Stefan Schulz, Institute of Pharmacology and Toxicology, Jena University Hospital - Friedrich Schiller University Jena, Drackendorfer Straße 1, D-07747 Jena, Germany. E-mail: [email protected] This work was supported by the Deutsche Forschungsgemeinschaft [Grant GRK 1459 to H.-J.K.; Grants SCHU924/10-3, SCHU924/14-1, and SFB/TR166-TPC5 to S.S.]; the Deutsche Krebshilfe [Grant 109952 to S.S.]; the Inserm and Paris Diderot University to P.D. and Z.C.; the French National Institute for Cancer Research [INCa Grants 2013-102 and 2015-115 to C.B.]; the French Ligue Nationale Contre le Cancer [Grant Equipe Labellisée to C.B.]; the Université Fédérale de Toulouse [Grant U1037-G16001BB-IDEX to C.B.]; the University of Brescia [Grants 2015 and 2016_DMMT_Tulipano_EX60 to G.T.]; the Junta de Andalucia [Grants BIO-0139 and CTS-1406 to J.P.C.]; the MINECO [Grant BFU2016-80360-R to J.P.C.]; the ISCIII [Grant PIE14-00005, CIBERobn to J.P.C.], the GETNE [Grant 2014, SAEDYN Grant 2016 to J.P.C.]; the Medical Research Council and EU FP7 to M.K.; the National Institutes of Health [Grant DK103198 to S.M.]; and the Doris Factor Molecular Endocrinology Laboratory at Cedars-Sinai Medical Center. G.T. has received research grants (2009 and 2015) from Novartis Farma (Italy). C.B. has received research grants (2012–2017) from Novartis. M.K. has received research grants and lecture fees from Pfizer and Ipsen, and is a consultant for Ono, Heptares, Ferring, and Pfizer. J.P.C. has received research grants and lecture fees from Novartis and Ipsen, and is listed as inventor of patent PCT/ES2007/00627. M.C. was previously employed by Ipsen. S.M. has received research grants from Pfizer and Ipsen, and is a consultant for Chiasma, Novartis, Ionis, Ono, Strongbridge, and Midatech. S.S. has received research grants and lecture fees (2006–2017) from Novartis, Ipsen, Aspireo, Italfarmaco, and Strongbridge. T.G., P.D., Z.C., H.-J.K., A.L., and H.-J.W. have nothing to disclose. https://doi.org/10.1124/pr.117.015388. 763 764 Günther et al. F. Somatostatin Receptor 1 Function.......................................................777 G. Somatostatin Receptor 1 Ligands. ......................................................779 V. Somatostatin Receptor 2 . ..................................................................779 A. Somatostatin Receptor 2 Structure......................................................779 B. Somatostatin Receptor 2 Signaling Mechanisms . .....................................780 C. Somatostatin Receptor 2 Regulation.....................................................782 D. Somatostatin Receptor 2 Trafficking....................................................783 E. Somatostatin Receptor 2 Interacting Proteins. ..........................................784 F. Somatostatin Receptor 2 Anatomic Framework .........................................785 1. Central and Peripheral Nervous System. ..........................................785 2. Pituitary . ........................................................................785 3. Peripheral Organs ..................................................................785 4. Tumors.............................................................................785 G. Somatostatin Receptor 2 Function.......................................................787 1. Endocrine System ..................................................................787 2. Central Nervous System ............................................................787 a. Neuronal excitability and epilepsy ...............................................787 b. Motor control. ..................................................................787 c. Feeding and drinking............................................................787 d. Stress response..................................................................788 3. Retina..............................................................................788 H. Somatostatin Receptor 2 Ligands. ......................................................788 VI. Somatostatin Receptor 3 . ..................................................................788 A. Somatostatin Receptor 3 Structure......................................................788 B. Somatostatin Receptor 3 Signaling Mechanisms . .....................................789 C. Somatostatin Receptor 3 Regulation.....................................................789 D. Somatostatin Receptor 3 Trafficking....................................................790 E. Somatostatin Receptor 3 Targeting......................................................791 F. Somatostatin Receptor 3 Interacting Proteins. ..........................................792 G. Somatostatin Receptor 3 Anatomic Framework .........................................792 H. Somatostatin Receptor 3 Function.......................................................793 I. Somatostatin Receptor 3 Ligands. ......................................................793 VII. Somatostatin Receptor 4 . ..................................................................793 A. Somatostatin Receptor 4 Structure......................................................793 B. Somatostatin Receptor 4 Signaling Mechanisms . .....................................794 C. Somatostatin Receptor 4 Regulation.....................................................794 ABBREVIATIONS: ACTH, adrenocorticotropic hormone; AIP, aryl hydrocarbon receptor-interacting protein; AP, activator protein; ARC, arcuate nucleus; BBS, Bardet–Biedl syndrome; CA, Cornu Ammonis; CCK, cholecystokinin; CD26, dipeptidyl peptidase-4/cluster of differentiation 26; CHO, Chinese hamster ovary; CNS, central nervous system; CRF, corticotropin-releasing factor; CRH, corticotropin- releasing hormone; CST, cortistatin; D2 receptor, dopamine receptor D2; DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic