VIP

Mechanism (as reported)

Mechanistic research reported that VIP actions are mediated through receptor-mediated signaling that includes activation of cAMP-linked pathways. (PMIDs: 2698176, 12388623, 11145597) Pharmacophore mapping work investigated VIP interactions with VPAC(2) receptors using amino-acid scanning approaches and identified residues implicated in high-affinity potency (including Asp(3), Phe(6), Thr(7), Tyr(10), Arg(12), Tyr(22), and Leu(23)), with reported species and experimental-system differences. (PMID: 12388623)

Key findings (each cites a source)

• VIP was described as being derived from a 170 amino acid precursor processed into multiple preproVIP-derived peptides including preproVIP 22-79, PHI, preproVIP 111-122, and preproVIP 156-170. [PMID 19859678]
• PreproVIP-derived peptides were reported to be present in normal tissue and in VIP-producing cell lines, with elevated quantities detected in plasma and tumor tissues from patients with VIP-producing tumors. [PMID 19859678]
• In some tissues, a dibasic cleavage site after PHI was reported to be uncleaved, producing a C-terminally extended form (PHV). [PMID 19859678]
• A study reported PHI and VIP were present in a 1:1 molar ratio in large dense core vesicles and released in roughly equimolar amounts. [PMID 19859678]
• Carboxyamidation of VIP and PHI was reported not to be critical, with glycine-extended forms of both peptides demonstrated. [PMID 19859678]
• PACAP was described as being derived from a 170 amino acid precursor giving rise to PACAP 38, PACAP 27, and PRP, with PACAP 38 reported as the dominating form. [PMID 19859678]
• Research on PACAP processing reported that prohormone convertase (PC) 1 and 2 seem to be involved, except in testes and ovary where the PACAP precursor was reported as a substrate for PC4. [PMID 19859678]
• A review reported VIP as a major regulatory peptide in the mammalian brain with described roles spanning neurotransmitter and hormonal functions, and as acting via receptor-mediated systems including cAMP-linked signaling pathways. [PMID 2698176]
• A study investigating VIP receptor subtypes in osteoblasts reported rank order of cAMP response as PACAP 38 > PACAP 27 > helodermin > VIP > helospectin > glucagon > PHI >>> secretin. [PMID 11145597]
• In mouse calvarial osteoblasts, VIP-2 receptor expression was reported with higher affinity binding for PACAP 38 than for VIP, and VIP-1 receptor expression was reported as induced during osteoblastic differentiation. [PMID 11145597]
• A pharmacophore study reported residues most important for high affinity potency for VPAC(2) included Asp(3), Phe(6), Thr(7), Tyr(10), Arg(12), Tyr(22), and Leu(23), and reported non-essential residues including Ser(2), Asp(8), Asn(9), Gln(16), Val(19), Lys(20), Lys(21), Asn(24), and Ser(25). [PMID 12388623]
• The VPAC(2) pharmacophore study reported significant species differences and differences associated with the receptor expression system (e.g., CHO vs Sup T(1) or PANC1 cells). [PMID 12388623]