Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [5-6]) are activated by the endogenous peptides VIP (VIP, P01282), PACAP-38 (ADCYAP1, P18509), PACAP-27 (ADCYAP1, P18509), peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM (VIP, P01282)) and peptide histidine valine (PHV (VIP, P01282)). VPAC₁ and VPAC₂ receptors display comparable affinity for the PACAP peptides, PACAP-27 (ADCYAP1, P18509) and PACAP-38 (ADCYAP1, P18509), and VIP (VIP, P01282), whereas PACAP-27 (ADCYAP1, P18509) and PACAP-38 (ADCYAP1, P18509) are >100 fold more potent than VIP (VIP, P01282) as agonists of most isoforms of the PAC₁ receptor. However, one splice variant of the human PAC₁ receptor has been reported to respond to PACAP-38 (ADCYAP1, P18509), PACAP-27 (ADCYAP1, P18509) and VIP (VIP, P01282) with comparable affinity [1]. PG 99-465 [9] has been used as a selective VPAC₂ receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC₁ and PAC₁ receptors [2]. The selective PAC₁ receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP (VIP, P01282) or the PACAP peptides [10]. Two deletion variants of maxadilan, M65 [15] and Max.d.4 [11] have been reported to be PAC₁ receptor antagonists, but these peptides have not been extensively characterised.

Subtypes of PAC₁ receptors have been proposed based on tissue differences in the potencies of PACAP-27 (ADCYAP1, P18509) and PACAP-38 (ADCYAP1, P18509); these might result from differences in G protein coupling and second messenger mechanisms [16], or from alternative splicing of PAC₁ receptor mRNA [14].

* Key recommended reading is highlighted with an asterisk

Couvineau A, Ceraudo E, Tan YV, Laburthe M. (2010) VPAC1 receptor binding site: contribution of photoaffinity labeling approach. Neuropeptides, 44 (2): 127-32. [PMID:20031208]

Dias BG, Ressler KJ. (2013) PACAP and the PAC1 receptor in post-traumatic stress disorder. Neuropsychopharmacology, 38 (1): 245-6. [PMID:23147486]

Dickson L, Finlayson K. (2009) VPAC and PAC receptors: From ligands to function. Pharmacol Ther, 121 (3): 294-316. [PMID:19109992]

Gonzalez-Rey E, Varela N, Chorny A, Delgado M. (2007) Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator. Curr Pharm Des, 13 (11): 1113-39. [PMID:17430175]

Groneberg DA, Rabe KF, Fischer A. (2006) Novel concepts of neuropeptide-based drug therapy: vasoactive intestinal polypeptide and its receptors. Eur J Pharmacol, 533 (1-3): 182-94. [PMID:16473346]

* Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, Rawlings SR, Robberecht P, Said SI, Sreedharan SP et al.. (1998) International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev, 50 (2): 265-70. [PMID:9647867]

* Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI. (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol, 166 (1): 4-17. [PMID:22289055]

Hill JM. (2007) Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential. Curr Pharm Des, 13 (11): 1079-89. [PMID:17430171]

Laburthe M, Couvineau A, Tan V. (2007) Class II G protein-coupled receptors for VIP and PACAP: structure, models of activation and pharmacology. Peptides, 28 (9): 1631-9. [PMID:17574305]

Moody TW, Ito T, Osefo N, Jensen RT. (2011) VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies. Curr Opin Endocrinol Diabetes Obes, 18 (1): 61-7. [PMID:21157320]

Nakata M, Yada T. (2007) PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential. Curr Pharm Des, 13 (11): 1105-12. [PMID:17430174]

* Reglodi D, Kiss P, Horvath G, Lubics A, Laszlo E, Tamas A, Racz B, Szakaly P. (2012) Effects of pituitary adenylate cyclase activating polypeptide in the urinary system, with special emphasis on its protective effects in the kidney. Neuropeptides, 46 (2): 61-70. [PMID:21621841]

Schytz HW, Olesen J, Ashina M. (2010) The PACAP receptor: a novel target for migraine treatment. Neurotherapeutics, 7 (2): 191-6. [PMID:20430318]

* Smith CB, Eiden LE. (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse?. J Mol Neurosci, 48 (2): 403-12. [PMID:22610912]

Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L et al.. (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev, 61 (3): 283-357. [PMID:19805477]

1. Dautzenberg FM, Mevenkamp G, Wille S, Hauger RL. (1999) N-terminal splice variants of the type I PACAP receptor: isolation, characterization and ligand binding/selectivity determinants. J Neuroendocrinol, 11 (12): 941-9. [PMID:10583729]

2. Dickson L, Aramori I, McCulloch J, Sharkey J, Finlayson K. (2006) A systematic comparison of intracellular cyclic AMP and calcium signalling highlights complexities in human VPAC/PAC receptor pharmacology. Neuropharmacology, 51 (6): 1086-98. [PMID:16930633]

3. Gourlet P, De Neef P, Cnudde J, Waelbroeck M, Robberecht P. (1997) In vitro properties of a high affinity selective antagonist of the VIP1 receptor. Peptides, 18 (10): 1555-60. [PMID:9437716]

4. Gourlet P, Vertongen P, Vandermeers A, Vandermeers-Piret MC, Rathe J, De Neef P, Waelbroeck M, Robberecht P. (1997) The long-acting vasoactive intestinal polypeptide agonist RO 25-1553 is highly selective of the VIP2 receptor subclass. Peptides, 18 (3): 403-8. [PMID:9145428]

5. Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, Rawlings SR, Robberecht P, Said SI, Sreedharan SP et al.. (1998) International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev, 50 (2): 265-70. [PMID:9647867]

6. Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI. (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol, 166 (1): 4-17. [PMID:22289055]

7. Juarranz MG, Van Rampelbergh J, Gourlet P, De Neef P, Cnudde J, Robberecht P, Waelbroeck M. (1999) Different vasoactive intestinal polypeptide receptor domains are involved in the selective recognition of two VPAC(2)-selective ligands. Mol Pharmacol, 56 (6): 1280-7. [PMID:10570056]

8. Moody TW, Jensen RT, Fridkin M, Gozes I. (2002) (N-stearyl, norleucine17)VIPhybrid is a broad spectrum vasoactive intestinal peptide receptor antagonist. J Mol Neurosci, 18 (1-2): 29-35. [PMID:11931347]

9. Moreno D, Gourlet P, De Neef P, Cnudde J, Waelbroeck M, Robberecht P. (2000) Development of selective agonists and antagonists for the human vasoactive intestinal polypeptide VPAC(2) receptor. Peptides, 21 (10): 1543-9. [PMID:11068102]

10. Moro O, Lerner EA. (1997) Maxadilan, the vasodilator from sand flies, is a specific pituitary adenylate cyclase activating peptide type I receptor agonist. J Biol Chem, 272 (2): 966-70. [PMID:8995389]

11. Moro O, Wakita K, Ohnuma M, Denda S, Lerner EA, Tajima M. (1999) Functional characterization of structural alterations in the sequence of the vasodilatory peptide maxadilan yields a pituitary adenylate cyclase-activating peptide type 1 receptor-specific antagonist. J Biol Chem, 274 (33): 23103-10. [PMID:10438479]

12. Nicole P, Lins L, Rouyer-Fessard C, Drouot C, Fulcrand P, Thomas A, Couvineau A, Martinez J, Brasseur R, Laburthe M. (2000) Identification of key residues for interaction of vasoactive intestinal peptide with human VPAC1 and VPAC2 receptors and development of a highly selective VPAC1 receptor agonist. Alanine scanning and molecular modeling of the peptide. J Biol Chem, 275 (31): 24003-12. [PMID:10801840]

13. Pisegna JR, Lyu RM, Germano PM. (2000) Essential structural motif in the C-terminus of the PACAP type I receptor for signal transduction and internalization. Ann N Y Acad Sci, 921: 195-201. [PMID:11193823]

14. Spengler D, Waeber C, Pantaloni C, Holsboer F, Bockaert J, Seeburg PH, Journot L. (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature, 365 (6442): 170-5. [PMID:8396727]

15. Uchida D, Tatsuno I, Tanaka T, Hirai A, Saito Y, Moro O, Tajima M. (1998) Maxadilan is a specific agonist and its deleted peptide (M65) is a specific antagonist for PACAP type 1 receptor. Ann N Y Acad Sci, 865: 253-8. [PMID:9928019]

16. Van Rampelbergh J, Gourlet P, De Neef P, Robberecht P, Waelbroeck M. (1996) Properties of the pituitary adenylate cyclase-activating polypeptide I and II receptors, vasoactive intestinal peptide1, and chimeric amino-terminal pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal peptide1 receptors: evidence for multiple receptor states. Mol Pharmacol, 50 (6): 1596-604. [PMID:8967982]

17. Xia M, Sreedharan SP, Bolin DR, Gaufo GO, Goetzl EJ. (1997) Novel cyclic peptide agonist of high potency and selectivity for the type II vasoactive intestinal peptide receptor. J Pharmacol Exp Ther, 281 (2): 629-33. [PMID:9152366]

Subcommittee members: Joseph R. Pisegna (Chairperson) CURE: Digestive Diseases Research Centre Building 115 Room 315 West LA VA Medical Center University of California 11301 Wilshire Boulevard Los Angeles CA 90073 USA Jan Fahrenkrug University of Copenhagen Bispebjerg Bakke 23 DK2400 NV Copenhagen Denmark Illana Gozes Department of Clinical Biochemistry Sackler School of Medicine Tel Aviv University Ramat Aviv 69978 Israel Marc Laburthe INSERM Centre de Recherche Biomédicale Bichat-Beaujon (CRB3) Faculté de Médecine Xavier Bichat BP 416 16 rue Henri Huchard Paris Cedex 18 75870 France Victor May Department of Anatomy and Neurobiology University of Vermont College of Medicine 149 Beaumont Avenue, HRSF 428 Burlington VT 05405 USA Hubert Vaudry Inserm U982 Institute for Research and Innovation in Biomedicine (IRIB) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Team Neurotrophic Factors and Neuronal Differentiation Associated International Laboratory Samuel de Champlain Regional Platform for Cell Imaging of Haute-Normandie (PRIMACEN) Normandy University F-76000 Rouen, France David Vaudry INSERM Unit 982 Institute for Research and Innovation in Biomedicine (IRIB) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Team Neurotrophic Factors and Neuronal Differentiation Associated International Laboratory Samuel de Champlain Regional Platform for Cell Imaging of Haute-Normandy (PRIMACEN) Normandy University F-76821 Mont-Saint-Aignan, France James A. Waschek Department of Psychiatry University of California Los Angeles 635 Charles E. Young Dr. South, Room NRB 345 Los Angeles CA 90095-7332 USA

Other contributors: Edward J. Goetzl Departments of Medicine and Microbiology-Immunology UCSF 533 Parnassus at 4th San Francisco California 94143-0711 USA Anthony Harmar (Past chairperson) (1951-2014) formerly of the University of Edinburgh, Edinburgh, Scotland Sami I. Said (1928-2013) formerly of Departments of Medicine Physiology and Graduate Program in Pharmacology Pulmonary/Critical Care Medicine State University of New York at Stony Brook School of Medicine Health Sciences Center T17-025 Stony Brook New York 11794-8172 USA