Vasoactive intestinal peptide (VIP) is a 28-amino acid polypeptide first isolated from swine duodenum. VIP is a neurotransmitter that is extensively distributed in tissues. According to published reports, VPAC1 and VPAC2 act as VIP receptors and are widely present in the central nervous system and peripheral tissues. VIP exerts diverse actions on the cardiovascular system, pancreas, digestive tract, respiratory system, and urological system. Recent reports indicated that VIP has immunological and neuroprotective effects and also affects cell growth. While primary investigations for developing therapeutic applications for various pathological conditions and diseases are underway, the structure and function of VIP should be analyzed in more detail.
Vasoactive intestinal peptide (VIP) is a 28-amino acid polypeptide that was first isolated from swine duodenum about 40 years ago. The polypeptide derived its name because of its vasodilating action, which modifies the intestinal blood flow [1]. VIP was first classified as an intestinal hormone because it was isolated from the digestive tract and plays a role in electrolyte secretion in the intestinal tract, but it was subsequently found to be extensively distributed as a neurotransmitter in tissues [2]. VIP derived from pigs, cows, and rats have the same structure. Furthermore, VIP released from endocrine cells in the central nerve, peripheral nerve, digestive tract, or pancreas has the same structure. VIP exerts neural modulating activity on secretion, gastrointestinal motility, and blood flow in the pancreas and intestine, and the peptide shows similar activities in the cardiovascular, respiratory, and urological systems [2]. Recent reports have described a broader range of activities, such as immunological and neuroprotective effects [2]. While preliminary investigations for the development of therapeutic applications for various pathological conditions and diseases are underway, the structure and function of the protein needs to be analyzed in greater detail for this purpose.
In this review, we have discussed current information on VIP and its receptors and included new findings.
2. Structure of VIP
Since the amino acid sequence of VIP is very similar to that of secretin and glucagon, it was formerly classified with these peptides in the secretin peptide family [2]. The structure of VIP is similar to that of numerous other peptides, including pituitary adenylate cyclase activity peptide (PACAP), peptide histidine isoleucine or methionine (PHI or PHM), growth hormone-releasing factor (GRF), and glucagon-like peptide (GLP) as well as non-mammalian helospectin I, helospectin II, helodermin, exendin-3, and exendin-4 (Figure 1). VIP has 70% homology with PACAP27, with 19 amino acids in common, 50% homology to PACAP38, with 9 amino acids in common, and 33% homology with secretin. PHI, a VIP-related peptide, was isolated from swine small intestine, and along with PHM, it shares 48% amino acid homology
with VIP. PHI/PHM is produced by posttranslational processing of the VIP precursor, as discussed later [3].
When VIP was analyzed by circular dichroism (CD) or nuclear magnetic resonance (NMR) spectroscopy, it was shown to have a helical conformation with an α-helix (residues 11 - 26) and 2 β-bends (residues 2 - 5 and 1 - 10) at the N-terminus [4] (Figure 2). The N-terminal and C-terminal domains are believed to be important for bioactivity and receptor recognition.
Fifteen years ago, the human VIP gene was cloned and mapped to chromosome 6q25 (Figure 3) [2]. The human VIP precursor gene consists of 7 exons and 6 introns [3]. A signal peptide consisting of 21 amino acids is located in the second exon. PHM is encoded by the fourth exon, and VIP is encoded by the fifth exon; VIP and PHM are produced after processing [3].
While VIP is soluble in water and aqueous organic solvents, its activity is lowered by oxidization because of the inclusion of a methionine residue. An aqueous solution of VIP is relatively unstable. VIP is easily degraded as its half-life in vivo is less than 1 min [5].
3. Structure of Receptor
G protein-coupled 7 transmembrane receptors comprise the G protein-coupled receptor (GPCR) family and are classified into 3 groups (A, B, and C) [2]. The VIP/ PACAP receptor belongs to group B of the GPCR family and consists of 437 - 459 amino acid residues with an extracellular long-chain N-terminal domain (≥120 amino acid residues). In the extracellular domain, an asparagine-linked glycosylation site is paired with the cysteine residue, and the first and second extracellular domains form a disulfide bond [6].
According to the IUPHAR (International Union of Pharmacology) Classification [7] issued in 1998 (Table 1), mammals have 2 subtypes of VIP receptors (VPACs), namely, VPAC1 and VPAC2.
Figure 4 shows the amino acid sequence and the GenBank accession number of human VPACs extrapolated from the nucleotide sequence. Human VPAC1 [8] and VPAC2 [9] have 457 and 438 amino acid residues, respectively. Rat VPAC1 [10] and VPAC2 [11] have 459
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