Vasoactive intestinal peptide (VIP) is an amidated 28 amino acid peptide first isolated from porcine duodenum. It functions as a neurotransmitter and neuroendocrine hormone, activating adenylate cyclase through G protein-coupled receptors. VIP has a number of actions in the periphery, including vascular and non-vascular smooth muscle relaxation, vasodilatation and electrolyte secretion. In addition, it has also been shown to possess both anti-inflammatory and anti-apoptotic properties. The presence of VIP and VIP receptors in defined pathways in brain indicates that it may play important roles in CNS function, including regulation of cerebral energy metabolism, cerebral blood flow, neuronal survival and control of circadian rhythms. Exogenous VIP stimulates prolactin secretion from the pituitary, catecholamine release from the adrenal medulla and insulin secretion from pancreatic islets. In the immune system, it inhibits mitogen-activated proliferation of T cells by inhibiting interleukin-2 production. Its anti-inflammatory and anti-injury effects have been demonstrated at several sites and include inhibition of TNF-α and other pro-inflammatory cytokines, and suppression of nuclear transcription factor NFκB activation. VIP is present in the ovary where it has been shown to stimulate oocyte maturation. Finally, it has also been shown to induce steroidogenesis in the adrenal medulla.

Pituitary adenylyl cyclase activating polypeptide (PACAP) was identified and purified on the basis of its ability to stimulate the accumulation of cAMP in rat pituitary cells in culture. Two forms of PACAP have been isolated from the hypothalamus, one of 38 amino acids (PACAP-38) and a C-terminally truncated form of 27 amino acids (PACAP-27). PACAP is closely related to VIP (68% sequence homology within the N-terminal 28 residues) and more distantly related to glucagon, glucagon-like peptide I (GLP), peptide histidine isoleucine amide (PHI), secretin and growth hormone releasing factor (GRF). PACAP has a distinct distribution in the central and peripheral nervous systems, where it is thought to function as a neurotransmitter. In addition, PACAP has been proposed to control the synthesis and secretion of catecholamines from the adrenal medulla and to regulate pancreatic exocrine activity. The presence of PACAP receptors in the reproductive tract has led to the suggestion that PACAP may have a role in the control of spermatogenesis.

Receptors for VIP and PACAP are members of a distinct family of seven transmembrane domain receptors coupled to G proteins. Other members of this family include receptors for secretin, growth hormone releasing factor, glucagon, glucagon-like peptide, calcitonin, calcitonin gene-related peptide, parathyroid hormone and corticotrophin releasing factor. PACAP exhibits a high affinity for three distinct receptors (PAC1, VPAC1 and VPAC2 receptors). Two of these, VPAC1 and VPAC2, are also high affinity receptors for VIP. The three receptors are preferentially coupled to Gs (adenylyl cyclase activation); the PAC1, VPAC1 and VPAC2 (with lower efficiency) are also coupled to Gq, Gi/Gq and Gq, respectively (calcium mobilization). In man, the chromosomal location is 7p15-p14, 3p22 and 7q36.3 for PAC1, VPAC1 and VPAC2 receptors, respectively. mRNA encoding the PAC1 receptor is found predominantly in CNS and adrenal medulla. mRNA encoding VPAC1 and VPAC2 receptors is widely distributed in the CNS and in peripheral tissues. In immune cells, VPAC1 receptor is constitutively expressed, whereas VPAC2 receptor expression is induced by immunological stimuli such as lipopolysaccharide. As tissue expression is in part overlapping, only some studies allow attributing to a receptor subtype precise physiological effects. Splice variants are described for the PAC1 receptor although their physiological significance is not yet fully established. A deletion mutant of mouse VPAC2 receptor, lacking 13 amino acids in the seventh transmembrane domain, has also been identified in immune cells. This mutant is expressed at the cell surface, binds VIP with high affinity but fails to transduce VIP induced signaling in immune cells. PAC1, VPAC1 and VPAC2 receptors have been proposed as potential targets for treatment of inflammation, autoimmunity, organ failure, neurodegeneration and pulmonary hypertension.

Table 1.Accepted modulators and additional information

Footnotes

a) Secretin, GRF and PHI interact with VPAC1 receptor, probably at supraphysiological concentrations.

b) Displays significant affinity for VPAC2 receptors.

Abbreviations

GRF: Growth hormone releasing factor
PACAP: Pituitary adenylyl cyclase activating peptide
PHI: Peptide Histidine Isoleucine-amide
Ro 25-1553: Ac-His1[Glu8,Lys12,Nle17,Ala19,Asp25,Leu26,Lys27,28,Gly29,30,Thr31]-NH2 VIP (cyclo-21-25)
Ro 25-1392: Ac-His1[Glu8,OCH3-Tyr10,Lys12,Nle17,Ala19,Asp25,Leu26,Lys27,28] VIP (cyclo-21-25)
PG 99-465: Myr-His1[Lys12,Lys27,28,Gly29,30,Thr31]-NH2 VIP
VIP: Vasoactive intestinal peptide

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