GLP-2R

GLP-2R is the class B GPCR for GLP-2 - the intestinotrophic proglucagon-derived hormone that drives small bowel mucosal growth, crypt cell proliferation, and gut barrier integrity. GLP-2 and GLP-1 are co-secreted from the same enteroendocrine L cells after meals; GLP-2R agonism is the pharmacological basis for treating short bowel syndrome (SBS) and is under investigation for inflammatory bowel disease and intestinal adaptation. Teduglutide (a DPP-4-resistant GLP-2 analog) is approved. This card defines the scaffold space for gut-restorative and intestinal barrier peptides.

Receptor structure and signaling

GLP-2 (33 aa: His-Ala-Asp-Gly-Ser-Phe-Ser-Asp...) is processed from proglucagon in intestinal L cells by PC1/3 (not PC2, which makes glucagon in pancreatic alpha cells). The N-terminal His-Ala dipeptide makes native GLP-2 susceptible to DPP-4 cleavage (plasma half-life ~7 minutes). GLP-2R (cloned 1999) is a canonical class B GPCR: large N-terminal ECD for C-terminal GLP-2 helix capture, TM bundle for N-terminal GLP-2 activation, Gs → adenylyl cyclase → cAMP → PKA. Highest GLP-2R expression: jejunum and ileum of enteric neurons, subepithelial myofibroblasts, and enteroendocrine cells - not epithelial cells directly. Downstream proliferative effects are paracrine: PKA-independent EGFR transactivation → MAPK/ERK; IGF-1 upregulation in myofibroblasts → IGF-1R crosstalk; PI3K/Akt → mTOR. Anti-apoptotic: Bcl-2 upregulation, caspase suppression via GSK-3β/Bad. GLP-2 also delays gastric emptying, inhibits gastric acid secretion, and modulates gut motility through enteric neural pathways.

Approved drugs and research scaffolds

Teduglutide (GLP-2 with Gly at position 2 replacing Ala, DPP-4-resistant) is FDA-approved for adults and children with SBS-dependent parenteral nutrition, reducing PN volume by 20–40% in clinical trials. Apraglutide (longer-acting GLP-2 analog with fatty acid conjugation for weekly dosing) is in Phase 3 for SBS. Glepaglutide is another long-acting analog in development. For peptide research, the tractable recipes are: position-2 Gly or Aib substitutions to block DPP-4 cleavage while preserving receptor potency; C-terminal extensions or fatty acid conjugations (analogous to semaglutide's approach) for extended half-life; GLP-1/GLP-2 dual agonist scaffolds that combine L-cell hormones into a single molecule for combined metabolic and intestinal effects; and GLP-2R biased agonists that maximize crypt proliferation over motility suppression to improve clinical utility in SBS.