1521-0081/72/4/910–968$35.00 https://doi.org/10.1124/pr.120.019331 PHARMACOLOGICAL REVIEWS Pharmacol Rev 72:910–968, October 2020 Copyright © 2020 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. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2 Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions Xavier Norel,* Yukihiko Sugimoto,* Gulsev Ozen, Heba Abdelazeem, Yasmine Amgoud, Amel Bouhadoun, Wesam Bassiouni, Marie Goepp, Salma Mani, Hasanga D. Manikpurage, Amira Senbel, Dan Longrois, Akos Heinemann,* Chengcan Yao,* and Lucie H. Clapp* Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.) Abstract ...................................................................................912 Significance Statement. ..................................................................912 I. Introduction . ..............................................................................913 A. Updated Aspects of General Characteristics of Prostaglandin E2 Receptors 1–4 and Prostacyclin Receptors .................................................................913 1. Prostaglandin E2 Receptor 1 . ......................................................913 a. Prostaglandin E2 receptor 1 signaling . ..........................................913 2. Prostaglandin E2 Receptors 2 and 4 . ................................................915 b. Prostaglandin E2 receptor 2 and prostaglandin E2 receptor 4 signaling ...........915 3. Prostaglandin E2 Receptor 3 . ......................................................916 c. Prostaglandin E2 receptor 3 signaling . ..........................................916 4. Prostacyclin Receptor . ............................................................917 d. Prostacyclin receptor signaling. ................................................917 B. Single-Nucleotide Polymorphisms and Dimerization of Prostaglandin E2 Receptors 1–4 and Prostacyclin Receptors. ......................................................917 C. Crystal Structures of Human Prostaglandin E2 Receptor 3 and Prostaglandin E2 Receptor 4 .............................................................................918 D. Allosteric Modulators and Biased Ligands ..............................................918 II. Immune System . ........................................................................918 A. Effects of Prostaglandin E2 Receptors 1–4 and Prostacyclin Receptor on Human and Mouse Immune Cells. ..................................................................918 1. T Lymphocytes . ..................................................................918 Address correspondence to: Xavier Norel, Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, 75018 Paris, France. E-mail: [email protected] This work was supported in part by Medical Research Council (MRC) UK [MR/R008167/1 to C.Y.], Cancer Research United Kingdom (CRUK) [C63480/A25246 to C.Y.], grants from the Japan Agency for Medical Research and Development, and Grants-in-Aid for Scientific Research [22116003, 24390017, 15H05905, 17H03990, and 19K22503] from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y.S.), and European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant [665850 for an educational grant to H.A.]. *Asterisk indicates members of the NC-IUPHAR Prostanoid Receptors Subcommittee. https://doi.org/10.1124/pr.120.019331. 910 EP1–4 and IP Receptors in Human and Rodents 911 2. Innate Lymphoid Cells. ............................................................919 3. Dendritic Cells......................................................................919 4. Macrophages .......................................................................920 5. Neutrophils. ........................................................................920 6. Eosinophils and Mast Cells . ......................................................921 7. Hematopoietic Stem/Progenitor Cell and Leukemia . ...............................921 B. Roles of Prostaglandin E2 in Human Autoimmune Diseases and Relevant Mouse Models. ..............................................................................921 1. Multiple Sclerosis. ..................................................................922 2. Rheumatoid Arthritis . ............................................................922 3. Inflammatory Bowel Disease and Colon Cancer. .....................................922 4. Lung Inflammation .................................................................923 5. Skin Inflammation and Cancer......................................................924 III. Cardiovascular System. ..................................................................924 A. Healthy Condition . ..................................................................924 1. Vascular Tone Regulation ...........................................................924 B. Cardiovascular Diseases................................................................925 1. Hypertension .......................................................................925 2. Diabetes ............................................................................926 3. Abdominal Aortic Aneurysm . ......................................................927 4. Obesity .............................................................................928 5. Atherosclerosis . ..................................................................928 6. Cerebral Stroke. ..................................................................930 7. Arrhythmia. ........................................................................931 8. Pulmonary Circulation and Hypertension. ..........................................931 IV. Thrombosis . ..............................................................................933 A. Role of Prostaglandin E2 on Platelet Function ..........................................933 1. Expression of Prostaglandin E2 Receptors in Platelets ...............................933 2. Prostaglandin E2 and Prostaglandin E2 Receptor 2 . ...............................933 3. Prostaglandin E2 and Prostaglandin E2 Receptor 3 . ...............................934 4. Prostaglandin E2 and Prostaglandin E2 Receptor 4 . ...............................934 B. Role of Prostacyclin on Platelet Function ...............................................934 V. Central and Peripheral Nervous System....................................................935 A. Central Nervous System . ............................................................935 1. Alzheimer Disease ..................................................................935 2. Parkinson Disease ..................................................................936 3. Huntington Disease.................................................................936 4. Multiple Sclerosis in Central Nervous System . .....................................936 ABBREVIATIONS: AA, arachidonic acid; AAA, abdominal aortic aneurysm; AC, adenylate cyclase; AD, Alzheimer disease; Akt, protein kinase B; ALS, amyotrophic lateral sclerosis; Ang-II, angiotensin 2; APPS, Swedish amyloid precursor protein; Ab, b amyloid; BMP, bone morphogenetic protein; BMSC, bone marrow stromal cell; CCL, chemokine ligand; CD, cluster of differentiation; CES1, carboxylesterase 1; CML, chronic myelogenous leukemia; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; COX, cyclooxygenase; CRC, colorectal cancer; CREB, cAMP response element-binding protein; CSC, cigarette smoke condensate; CSF, cerebrospinal fluid; CXCL, C-X-C motif chemokine ligand; DC, dendritic cell; DRG, dorsal root ganglion; DSS, dextran sodium sulfate; EAE, experimental autoimmune encephalomyelitis; EP, prostaglandin E2 receptor; Epac, exchange protein directly activated by cAMP; ERK, extracellular receptor kinase; FP, prostaglandin F receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HBEC, human bronchial epithelial cell; HD, Hun- tington disease; HEK, human endothelial kidney; HPC, hematopoietic progenitor cell; HSC, hematopoietic stem cell; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin;