SCTR

SCTR is the class B GPCR for secretin - the 27-aa duodenal peptide hormone that Bayliss and Starling discovered in 1902 as the first hormone ever identified. SCTR drives pancreatic bicarbonate secretion in response to duodenal acidification, coordinates bile duct fluid output, and - more recently discovered - activates brown adipose tissue thermogenesis and hypothalamic satiety circuits that contribute ~10% of daily energy expenditure in rodents. Synthetic human secretin (ChiRhoStim) is FDA-approved as a diagnostic agent for pancreatic function testing. SCTR is also expressed in the heart, kidney, and CNS, where secretin acts as a neuropeptide. This card defines the scaffold space for duodenal hormone analogs and gut-brain axis peptide research.

SCTR (chromosome 2q14.1, ~449 aa) belongs to the secretin/glucagon receptor subfamily of class B GPCRs - it is most closely related to VIP/VPAC receptors and GHRHR. Secretin (His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH₂) engages SCTR via the canonical class B two-domain mechanism: the C-terminal α-helix docks into the ECD, and the N-terminal His1-Ser2-Asp3 region activates the TM bundle. Cryo-EM of the secretin-SCTR-Gs complex confirmed the helical conformation of secretin spanning residues ~5–24 in the bound state. Primary signaling: Gs → adenylyl cyclase → cAMP → PKA → CFTR activation in pancreatic duct epithelium → bicarbonate and water secretion; Gq/11 → IP3/Ca²⁺ in some cell types; β-arrestin → ERK. In brown adipose tissue, SCTR-cAMP drives UCP1/HSL-mediated thermogenesis as part of the postprandial energy expenditure response. In the hypothalamus, secretin suppresses food intake via ↓AgRP/↑POMC neurons. High-affinity antagonist peptide (Ki ~4 nM, designed in 2020) provides the first selective SCTR research tool for blocking signaling.

Approved: synthetic human secretin (ChiRhoStim, IV injection) is FDA-approved for diagnosis of gastrinoma (secretin stimulation test), diagnosis of pancreatic exocrine dysfunction, and facilitation of ERCP pancreatogram. It is one of the few peptide hormone diagnostics in active clinical use. Porcine secretin (Secretin-Ferring) was previously approved and widely used for the secretin stimulation test in Zollinger-Ellison syndrome. No SCTR-targeted therapeutic agonist or antagonist is approved. For peptide research, the tractable recipes are: N-terminal secretin(1-14) truncation analogs with Aib substitutions at positions 2, 7, and 13 for DPP-4 resistance and sustained Gs activation in pancreatic duct cells; C-terminal secretin(15-27) fragments that retain ECD binding for use as competitive antagonist scaffolds; secretin/VIP chimeras exploiting the ~30% homology at the N-terminus to tune SCTR vs. VPAC1/VPAC2 selectivity for gut vs. CNS applications; and fatty acid-conjugated secretin analogs (C18 albumin-binding) for prolonged pancreatic exocrine stimulation in chronic pancreatitis or exocrine pancreatic insufficiency.