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Questions And Answer

• Discovery

  VIP is a neuropeptide consisting of 28 aa residues, with wide distribution in the central and peripheral nervous systems. VIP has a broad spectrum of biologic actions, and acts as a neurotransmitter or neuromodulator and also as a hormone. VIP was first discovered as a smooth muscle-relaxant vasodilator peptide in the lung; it was isolated from the porcine intestine in 1970. Its original label as a “candidate gastrointestinal hormone” was soon replaced by its new and apparently true identity as a neuropeptide with neurotransmitter and neuromodulator properties.;

• Structure

  VIP possesses two segments of secondary structures: a random coil structure in the N-terminal region between positions 1 and 9, and a long α-helical structure in the C-terminal region stretching from position 10 to its C-terminus. The primary structure of VIP is highly conserved in vertebrates with complete identity among mammals except for the guinea pig and opossum. Mr 3326, pI >11. VIP is soluble in water to 20mg/mL.
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• Gene, mRNA, and precursor

  The human VIP gene, VIP, location 6q25.2, contains seven exons. Each exon encodes a distinct functional domain of the VIP precursor. The VIP precursor polypeptide (preproVIP) contains several additional biologically active peptides, including peptide histidine isoleucine (PHI, found in nonhuman mammals), peptide histidine methionine (PHM, the human equivalent of PHI), and peptide histidine valine (PHV, a C-terminally extended form of PHI and PHM).;

• Receptors

  VIP and PACAP share a wide spectrum of biological activity as well as common receptors belonging to the class II of GPCR. Three VIP or PACAP receptor types, which are derived from different genes, are recognized, namely VPAC1, VPAC2, and PAC1. Two of these receptors, VPAC1 and VPAC2, share a high binding affinity in the nanomolar range for VIP and PACAP. A third receptor type, PAC1, has been characterized for its high affinity for PACAP, but low affinity for VIP.;

• Synthesis and release

  VIP gene expression is stimulated by dibutyryl cAMP and by increased PKC activity induced by tumorpromoting phorbol esters. When acting together, cAMP and phorbol esters synergistically stimulate VIP gene transcription via different sites on the gene.;

• Signal transduction pathway

  By binding to VIP, VPAC acts on the Gs protein and activates PKA via elevation of AC activity and production of cAMP (cAMP-dependent pathway). PKA either inhibits phosphorylation of the downstream MAP/ERK kinase or promotes phosphorylation of cAMP response element binding protein (CREB), which finally leads to the inhibition of NF-κB. Meanwhile, studies have also identified a pathway that inhibits the nuclear entry of NF-κB through VPAC signaling, which inhibits IκB phosphorylation (cAMP-independent pathway).;

• Biological functions

  VIP is extensively distributed in central and peripheral tissues, where it acts as a neurotransmitter and neuromodulator.8 The main activity of VIP is vasodilatation. VIP induces the dilation of vessels, which results in increased blood flow, decreased peripheral vascular resistance, and hypotension. While VIP has a suppressive effect on the intestinal smooth muscle, it exerts relaxant effects on the lower esophageal sphincter, the sphincter of Oddi, the anal sphincter, and the bronchial smooth muscle. In the small intestine, VIP facilitates the secretion of electrolytes and aqueous liquid. In the stomach, it inhibits gastric secretion. In the pancreas, VIP facilitates the external secretion of bicarbonic acid and aqueous liquid from pancreatic epithelial cells, and facilitates enzyme secretion from acinar cells. VIP promotes the secretion of both insulin and glucagon in a glucose-dependent manner. VIP is broadly distributed in the central nervous system, especially in the hypothalamus and pituitary anterior lobe, and is associated with the regulation of pituitary hormones. VIP is produced by lymphoid tissue and exerts a wide spectrum of immunological functions, controlling the homeostasis of the immune system through different receptors expressed in various immunocompetent cells. VIP acts as a growth factor. It functions as a proliferative factor in normal tissue cells as well as in cancer cells. VIP might inhibit apoptosis by stimulating the expression of the apoptosis-inhibiting gene Bcl2 or by inhibiting the activity of caspase 3.;

• Clinical implications

  Various diseases have been reported to involve VIP activity, including bronchial asthma, transmission of pain, cluster headaches, Alzheimer’s disease, Parkinson’s disease, and brain injury.;

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