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Secretin Receptor Laurence J MOLECULE PAGE Secretin Receptor Laurence J. Miller and Maoqing Dong Department of Internal Medicine and the Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ e-mail: [email protected] Version 1.0, April 14, 2011 [DOI: 10.3998/panc.2011.12] Gene symbols: Sctr 1. General Structure and Function with six highly conserved cysteine residues that contribute to three structurally and functionally Secretin and its receptor hold special places in important intra-domain disulfide bonds, and seven history, with secretin representing the first hydrophobic transmembrane segments having “hormone”, giving rise to the field of endocrinology residue conservation quite distinct from other when W. M. Bayliss and E. H. Starling recognized family GPCRs (Fig. 1, left panel) (5-7). it as a blood-borne non-neural mediator of pancreatic exocrine secretion in 1902 (1), and In evaluation of these sequences, it has been with the secretin receptor cloned by T. Ishihara et proposed that the helical bundle of family B al. in 1991 (2), representing the first family B G GPCRs is structurally distinct from that of family A protein-coupled receptor and giving rise to this GPCRs (5-7), even though it still likely includes a new and important receptor family. heptahelical bundle conformation and is known to couple with the same group of heterotrimeric G The secretin receptor is a guanine nucleotide- proteins. It is noteworthy that family B GPCRs binding protein (G protein)-coupled receptor typically couple with both Gs and Gq, in contrast (GPCR) that binds to and is activated by the to family A GPCRs that often couple with only a peptide hormone, secretin. This receptor was the single dominant G protein. The extracellular first member of the B family of GPCRs (3, 4), amino-terminal tail domains of several members which also includes receptors for vasoactive of this receptor family have recently been intestinal polypeptide (VIP), pituitary adenylate structurally characterized, either by NMR or cyclase-activating peptide (PACAP), glucagon, crystallography, to exhibit a highly conserved core glucagon-like peptide (GLP), glucose-dependent that includes two anti-parallel β-sheets, three insulinotropic polypeptide (GIP), calcitonin, disulfide bonds, and variable amino-terminal α- calcitonin-like peptide, parathyroid hormone helix and multiple loop regions (8-17). The (PTH), corticotrophin-releasing factor (CRF), and structure also provides a conserved hydrophobic growth hormone releasing hormone (GHRH) (3, peptide-binding cleft above the stable core and 4). It is notable that these receptors lack the between the helix and loop regions. classical signature sequences found in most members of the much larger A family of GPCRs Like many GPCRs, the secretin receptor is (5, 6). The most typical features of B family glycosylated on ectodomains, predominantly GPCRs includes a long amino-terminal tail region within the amino-terminal tail, and also on the This work is subject to a Creative Commons Attribution 3.0 license. second extracellular loop (18). These all of these studies have been directed toward family represent sites of N-linked glycosylation of C or family A GPCRs, recent work has shown that asparagine residues. Site-directed mutagenesis it is relevant to family B GPCRs as well (22). The has demonstrated potential functional importance evidence is best for family C GPCRs, where of glycosylation on Asn72 and Asn291 of the human dimeric structures typically have profound effects secretin receptor (Fig 1 shows Asn78 and Asn263 on receptor function and specificity, and where of the rat sequence), representing the first of three crystal structures of covalently-bonded dimeric glycosylation sites within the amino-terminal tail complexes of ectodomains have been reported and the glycosylation site within the second (23). In family A GPCRs, there have been no extracellular loop, although selective, single consistent observations of which receptors might mutation of the other sites had no demonstrable associate with themselves or other GPCRs, of functional impact (18). Generally, the functional effects of oligomerization, or of the glycosylation sites of membrane receptors are impact of ligand binding on receptor important for proper folding during biosynthesis, oligomerization (23). The secretin receptor is ensuring normal trafficking, and for protecting the among the best studied family B GPCR in regard receptor from proteolytic degradation. to its oligomerization. It is constitutively present within homo-dimeric complexes determined by the Desensitization of GPCRs often can be induced lipid-exposed face of the fourth transmembrane both by biochemical modifications such as segment (24-26). This structure is critically phosphorylation and by cellular mechanisms such important for achieving the high affinity G protein- as internalization. The secretin receptor utilizes coupled state of this receptor, with non-dimerizing both of these. Like many receptors that activate mutants coupling less efficiently, binding secretin intracellular kinases, phosphorylation of the with lower affinity, and having less potent effects secretin receptor is utilized as a biochemical of secretin to stimulate cAMP (24-26). Of note, mechanism for feedback regulation involved in only the dimeric state of this receptor exhibits desensitization. Direct evidence for agonist- negative cooperativity (24), another protective stimulated phosphorylation of the secretin feature of some receptor systems. The receptor was first demonstrated by Ozcelebi et al. structurally specific nature of secretin receptor (19). That work established the phosphorylation homo-dimers appears to be consistent throughout of threonine and serine residues within the this receptor family (27). This receptor is also receptor carboxyl-terminal tail region. The able to form hetero-dimers with other family B kinases involved in phosphorylation of the GPCRs (28). secretin receptor were found to represent predominantly G protein-coupled receptor There is also a single report to demonstrate the kinases, with minor action by both protein kinase ability of the single transmembrane Receptor A and protein kinase C (20). Secretin receptor Activity-Modifying Protein-3 (RAMP-3) to phosphorylation has been shown to disrupt G associate with the secretin receptor during its protein coupling (21), but not to be necessary for biosynthesis (29). Of note, since the secretin agonist-induced receptor internalization (21). The receptor is able to traffick to the cell surface latter certainly occurs, and represents a major independent of its association with RAMPs, it is mechanism for desensitization of this receptor. difficult to identify a specific effect of this bimolecular association, unlike those members of In recent years, it has been recognized that the B family of GPCRs that cannot get to the cell certain GPCRs can associate with themselves surface without RAMPs, such as the calcitonin and with structurally related GPCRs to form receptor-like receptor (30). Indeed, no specific oligomeric or dimeric complexes (22). While most 2 functional effect has yet been demonstrated for receptors are expressed on essentially all cells RAMP-3 association with the secretin receptor within the kidney, with this hormone described to (29). stimulate renal blood flow and glomerular filtration rate, as well as tubular water reabsorption, and to Like secretin, all of the natural ligands of family B have effects on translocation of aquaporin (38, GPCRs, represent moderately long peptide 40). Secretin has been described to have both hormones having diffuse pharmacophoric diuretic and anti-diuretic effects, dependent on domains (3, 4). These all have the propensity to dose and route of administration (41). Secretin form helical structures, particularly in their receptors are also expressed on gastrointestinal carboxyl-terminal ends, a region of these peptides smooth muscle, neurons, and certain mucosal now known to bind to the hydrophobic cleft within cells, heart, and lung (39). the amino terminus of their receptors. This binding directs the amino-terminal region of these Like most family B GPCRs, the secretin receptor ligands toward the core helical bundle domain of is known to couple to both Gs and Gq, with the their receptors. This portion of secretin and other cAMP response to stimulation most prominent family B GPCR ligands is responsible for its and sensitive, while the intracellular calcium biological activity, with amino-terminally truncated responses are only observed with high forms of these ligands acting as antagonists (31- concentrations of hormone (42). The 33). The right panel of Figure 1 illustrates the determinants for G protein coupling have been current working model of secretin occupation of its best studied for family A GPCRs, where distinct binding site within the secretin receptor. motifs have been present in the juxtamembranous regions of the second and third intracellular loops The classical effects of secretin are the and carboxyl-terminal tail (43, 44). Some work stimulation of the secretion of bicarbonate, water, has been reported for family B GPCRs (45-47), and electrolytes from the pancreatic ductular but the same motifs in the same positions appear system, as well as the biliary ducts (34, 35). to be absent. It is interesting that the These effects are largely stimulated by secretin determinants for coupling with these two G released from S cells in the proximal intestine in proteins are
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