VPAC1

VPAC1 is the class B GPCR that mediates most of the immunomodulatory and secretory effects of vasoactive intestinal peptide (VIP) and PACAP-27/PACAP-38, expressed densely on immune cells (T lymphocytes, macrophages, dendritic cells), intestinal epithelium, liver, and lung. VIP acts as both a neurotransmitter in the enteric and autonomic nervous system and a hormone - it is the master brake on Th1/Th17 inflammatory responses and a potent driver of epithelial Cl⁻/HCO₃⁻ secretion. No VPAC1-selective peptide drug is approved for immune or GI indications, but VIP analogs for pulmonary hypertension were in Phase 3, and the target is under active investigation for inflammatory bowel disease, rheumatoid arthritis, and ARDS. This card covers VPAC1 specifically; VPAC2 (smooth muscle, pancreas, SCN) and PAC1 (CNS) share the same ligands but have distinct therapeutic profiles.

VPAC1 (chromosome 3p22.2, ~457 aa) is a Gs-primary class B GPCR that also couples to Gq in some cell types. VIP (His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂, 28 aa, C-terminal amide) binds VPAC1 and VPAC2 with comparable nanomolar affinity (Ki ~0.2–16 nM); PACAP-27 and PACAP-38 also bind both VPAC receptors at comparable affinity but bind PAC1 with ~1000-fold higher potency. The two-domain binding mechanism applies: VIP C-terminal α-helix (residues 6–26) docks into the ECD; N-terminal His1-Ser2-Asp3 activates the TM bundle. Primary signaling via VPAC1: Gs → adenylyl cyclase → cAMP → PKA → CREB → anti-inflammatory gene programs (IL-10↑, TNF-α↓, IL-6↓, IL-12↓) in immune cells; CFTR activation in epithelial cells → Cl⁻/HCO₃⁻ secretion. VPAC1-selective Gq coupling → PLC → Ca²⁺/PKC in some contexts (absent in VPAC2). β-arrestin → ERK; GRK2/3-mediated desensitization. VIP from enteric neurons is the primary neurotransmitter of non-adrenergic non-cholinergic (NANC) smooth muscle relaxation in the GI tract. In the immune system, VIP-VPAC1 signaling on regulatory T cells and tolerogenic dendritic cells drives suppression of Th1/Th17 responses and promotes Th2/Treg differentiation - mechanistically relevant for autoimmune and inflammatory diseases.

Approved: inhaled VIP (Aviptadil, IV/inhaled) reached Phase 3 for COVID-19 ARDS and pulmonary arterial hypertension; it received Emergency Use Authorization in some contexts but is not fully approved. No VPAC1-targeted drug is formally approved for immune or GI indications. Aviptadil demonstrated improvements in respiratory failure in early COVID-19 trials. For peptide research, the tractable recipes are: VIP N-terminal analog scanning (His¹→Tyr¹, Ser²→Aib², Asp³→Glu³) for DPP-4 resistance while preserving VPAC1 selectivity over PAC1 (critical for avoiding PACAP-like CNS effects); VPAC1/VPAC2 selectivity scans using N-terminal modifications and C-terminal truncations to isolate immune (VPAC1) from smooth muscle (VPAC2) pharmacology; PEGylated or lipidated VIP analogs for extended plasma half-life in autoimmune indications (native VIP t½ ~1 min); and cyclic lactam-constrained VIP analogs (ring closure at positions 10–14 to stabilize the active helix) for inhaled PAH therapy with reduced systemic vasodilation liability.