Secretin and vasoactive intestinal peptide receptors: Members of a unique family of G protein–coupled receptors  Charles D. Ulrich, Martin Holtmann‡, Laurence J. Miller‡  Gastroenterology  Volume 114, Issue 2, Pages 382-397 (February 1998) DOI: 10.1016/S0016-5085(98)70491-3 Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 1 General structural motifs of the two major families of G protein–coupled receptors: (A) the β-adrenergic receptor/rhodopsin family and (B) the secretin receptor family. Shown are the features typically conserved in these families. Both share the seven membrane-spanning helices and a prominent disulfide bond linking Cys residues in the first and second extracellular loops, but other “signature sequences” are quite divergent. Note the extended amino terminus of the secretin family receptors, which contains six highly conserved Cys residues, with at least a subset involved in disulfide bonding (pattern not yet established). Gastroenterology 1998 114, 382-397DOI: (10.1016/S0016-5085(98)70491-3) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 1 General structural motifs of the two major families of G protein–coupled receptors: (A) the β-adrenergic receptor/rhodopsin family and (B) the secretin receptor family. Shown are the features typically conserved in these families. Both share the seven membrane-spanning helices and a prominent disulfide bond linking Cys residues in the first and second extracellular loops, but other “signature sequences” are quite divergent. Note the extended amino terminus of the secretin family receptors, which contains six highly conserved Cys residues, with at least a subset involved in disulfide bonding (pattern not yet established). Gastroenterology 1998 114, 382-397DOI: (10.1016/S0016-5085(98)70491-3) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 2 Cycles of association and dissociation events involving heterotrimeric G protein components and ternary complexes of agonist ligand, receptor, and G protein. This series of events results in multiple independent opportunities to initiate and regulate signaling events, with Gα-GTP and Gβγ established mediators. GDP, guanosine diphosphate; H, hormone; R, receptor; R*, activated receptor. Gastroenterology 1998 114, 382-397DOI: (10.1016/S0016-5085(98)70491-3) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 3 Alignment of amino acid sequences of human receptors for secretin, VIP, glucagon, and calcitonin. Conserved residues are shown in capital letters; predicted transmembrane domains are shown below a bold line. #, Consensus sites of N-linked glycosylation; +, consensus sites of action of PKC; *, extracellular Cys residues. Gastroenterology 1998 114, 382-397DOI: (10.1016/S0016-5085(98)70491-3) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 4 Conceptualization of external surface of secretin family receptors, with transmembrane helices forming a cylindrical array and disulfide bonds establishing unique domains that could contribute potential binding sites and clefts. Because the disulfide bonding structure has not yet been established, the number and pattern illustrated are purely hypothetical. Gastroenterology 1998 114, 382-397DOI: (10.1016/S0016-5085(98)70491-3) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 5 Pathways that may regulate neoplastic growth of the pancreatic duct cell. Black arrows denote pathways known to regulate events in pancreatic carcinoma, and gray arrows represent other dominant pathways involved in tyrosine kinase receptor–stimulated growth in other cellular systems. AC, adenylyl cyclase; DAG, diacylglycerol; GF, growth factor; Gp, G protein; PI(3)K, phosphatidylinositol-3 kinase; PLD, phospholipase D; SOS, son of sevenless; TKR, tyrosine kinase receptor. Gastroenterology 1998 114, 382-397DOI: (10.1016/S0016-5085(98)70491-3) Copyright © 1998 American Gastroenterological Association Terms and Conditions