Vasoactive Vasoactive Intestinal Peptides (VIPs)、血管活性腸肽

Definition

Vasoactive can be defined as possessing the ability to alter the diameter or tension -- also called "tone" -- of blood vessels. Vasoactive chemicals may cause blood vessels to either dilate (widen) or constrict (narrow).

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid regulatory peptide with long-lasting relaxant effects on gastrointestinal and vascular smooth muscle. VIP is synthesized from a precursor molecule (prepro-VIP), which also contains peptide histidine methionine (PHM; in human tissues) or peptide histidine isoleucine (PHI; its counterpart in other mammalian species)1.

Discovery

VIP is a 28-amino acid peptide originally isolated from porcine duodenum by Said and Mutt2.

Structural Characteristics

The 170-amino acid prepro-VIP is metabolized by a signal peptidase in the endoplasmic reticulum to yield the 148-amino acid pro-VIP. Pro-VIP is cleaved by prohormone convertases to VIP-GKR (prepro-VIP125-155) and PHM-GKR (prepro-VIP81-110). VIP-GKR and PHM-GKR are then cleaved by carboxypeptidase-B-like enzymes to VIP-G and PHM-G. The VIP-G and PHM-G can then be metabolized by PAM enzymes to VIP and PHM, which have an amidated C terminus1. VIP is a 28-amino acid peptide with structural similarities with other gastrointestinal hormones, such as secretin, glucagon, gastric inhibitory peptide, PHM or PHI, growth hormone releasing hormone, helodermin, PACAP (which exists in two amidated forms, PACAP27 and PACAP38, and shows 68% identity with VIP), and corticotrophin releasing factor (CRF). Conformational analysis of VIP by two-dimensional NMR and circular dichroism spectroscopy has show an initial disordered N terminus sequence of eight amino acid residues, probably with two ß-turns, followed by two helical segments at residues 7 to 15 and 19 to 27 connected by a region of undefined structure that confers mobility to the peptide molecule3, 4.

Mode of Action

Effects of VIP are mediated through interaction with two receptors5: VPAC1 and VPAC2 . VIP may interact also with specific splice variants of pituitary adenylate cyclase activating polypeptide (PACAP) receptor (PAC1). The receptors for VIP and PACAP belong to family B or group II of the G-protein-coupled receptors (GPCRs), also called the secretin receptor family. VPAC1 and VPAC2 are preferentially coupled to Gas protein that stimulates increases in adenylate cyclase triggering a protein kinase A (PKA)-cAMP transduction pathway and activation of phospholipase C (PLC) and phospholipase D (PLD)5.

Analogs

Glycosylated VIP analogs: VIP is a prominent neuropeptide. However, the clinical applications of VIP are mainly hampered because of its rapid degradation in vivo. Peptide glycosylation is used to increase peptide resistance to proteolytic degradation and consequently increase peptide metabolic stability. Studies suggest the presence of three N-glycosylation sites on VIP receptor type 1 (VPAC1). Therefore, glycosylation of the VIP ligand could potentially increase its receptor affinity because of glyco–glyco interactions between the ligand and the receptor. In a study eight glycosylated VIP derivatives were synthesized to enhance VIP’s metabolic stability and to increase its ligand–receptor binding/activation. Each VIP analog was monoglycosylatedA by a monosaccharide addition to one amino-acid residue along the sequence. It was found that Glycosylation did not affect the a-helical structure shown by the native VIP in organic environment. Few glycosylated VIP analogs displayed highly potent VPAC1 receptor binding and cAMP-induced activation; only 4–6 fold lower in comparison to the native VIP. Furthermore, the peptide analog glycosylated on Thr11 ([11Glyc]VIP) showed a significantly enhanced stability toward trypsin enzymatic degradation in comparison to VIP. Analysis of the degradation products of [11Glyc]VIP showed that differently from VIP, incubation of the peptide [11Glyc]VIP with trypsin resulted in no cleavage at the Arg12–Leu13 peptide bond, suggesting that VIP glycosylation may lead to enhanced metabolic stability6.

Functions

VIP, a peptide produced by immune cells, exerts a wide spectrum of immunological functions that control the homeostasis of the immune system. VIP has been identified as a potent anti-inflammatory factor, both in innate and adaptive immunity. In innate immunity, this peptide inhibits the production of inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP reduces the expression of co-stimulatory molecules on antigen-presenting cells, and therefore reduces stimulation of antigen-specific CD4 T-cells. In terms of adaptive immunity, VIP promotes T-helper (Th)2-type responses, and reduces inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors are known. Therefore, VIP and its analogs have been proposed as promising alternative candidates to existing therapies for the treatment of acute, chronic inflammatory and autoimmune diseases.

References

Itoh M, Obata K, Yanaihara N, Okamoto H (1983) Human preprovasoactive intestinal polypeptide contains a novel PHI-27-like peptide, PHM-27. Nature, 304:547-549.

Said SI, Mutt V (1970). Polypeptide with broad biological activity: isolation from small intestine. Science, 169:1217-1218.

Fry DC, Madison VS, Bolin DR, Greeley DN, Toome V, Wegrzynski BB (1989). Solution structure of an analogue of vasoactive intestinal peptide as determined by two-dimensional NMR and circular dichroism spectroscopies and constrained molecular dynamics. Biochemistry, 28:2399-2409.

Theriault Y, Boulanger Y, St-Pierre S (1991) Structural determination of the vasoactive intestinal peptide by two dimensional H-NMR spectroscopy. Biopolymers, 31:459-464.

Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, Rawlings SR, Robberecht P, Said SI, Sreedharan SP, Wank SA, Waschek JA (1998). International union of pharmacology. XVIII.  Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol. Rev., 50(2): 265–270.    

Dangoor D, Biondi B, Gobbo M, Vachutinski Y, Fridkin M, Gozes I, Rocchi R (2008). Novel glycosylated VIP analogs: synthesis, biological activity and metabolic stability. Journal of Peptide Science, 14:321–328.

Gonzalez-Rey E, Delgado M (2005). Role of vasoactive intestinal peptide in inflammation and autoimmunity. Curr. Opin. Investig. Drugs., 6(11):1116-1123.