Vasoactive Intestinal Polypeptide VIP

5.2.1 Receptors

VIP is specifically recognized by members of a subfamily of G protein-coupled receptors (GPCRs). VIP binds to VPACt and VPAC2 with similar affinities (Kd = 3 to 10 nM) and PAC1 with much lower affinity (Kd = 1 |jM). VPAC1; VPAC2, and PAC, show a high level of homology to each other and share structural features, as a long N-terminus and short loops. As for most subfamilies of GPCRs, the greatest degree of homology is within the transmembrane domains and least in the N- and C-terminal segments. VPAC1 and VPAC2 are often expressed with reciprocal densities in one type of cell, and both show high levels of inducibility and repressibility. VIP receptors are presumed to transduce all of the effects of VIP but often act as mediators of other cytokines (Goetzl, Voice, and Dorsam 2001).

5.2.2 Gene Regulation

VIP is a 28 amino acid linear peptide with a C-terminal amide and without any complex substituents. Prepro VIP (VIP precursor) is also the source of biologically active peptide histidine isoleucine (PHI) or peptide histidine metionine (PHM). Human prepro VIP gene encoding is 8.8 Kb and has been localized in chromosome 6p24. Expression of prepro VIP is regulated with cell type specificity by intracellular cyclic AMP (cAMP) and Ca , phorbol esters, and several members of the neuropoietic family of cytokines (Yamagami et al. 1988; Fink, Verhave, Walton, Mandel, and Goodman 1991). Neural cell-specific full expression of the prepro VIP gene in mediated by a tissue-specific element consisting of a 452-bp domain with two AT-rich octamer-like sequences between -4.7 and 4.2 Kb upstream of the transcription start site (Hahm and Eiden 1998). Ca2+-mediated gene regulation increases in prepro VIP mRNA levels in human neuroblastoma cell lines contrast with those evoked by cAMP in being cAMP-independent, slower in time course and requiring de novo protein synthesis. Although increases in Ca2+ induce differential rises in several transcription factors relative to cAMP, no promoter element was unequivocally coupled to the effects of Ca2+ (Symes, Gearan, Eby, and Fink 1997).

VIP is expressed at levels predominantly determined by the balance between transcriptionally regulated synthesis and susceptibility to peptidolysis, and it exerts many different types of effects in numerous organ systems (Goetzl et al. 2001). It has been demonstrated that light affects VIP expression (Marshall and Born 2002) and that the prepro VIP mRNA display diurnal variations in the suprachiasmatic nucleus (SCN) after exogenous administration of VIP (Bredow, Kacsoh, Obal, Fang, and Krueger 1994). As a consequence, VIP affects the circadian clock, resulting in prolonged sleep cycles and earlier occurrence of the cortisol nadir (Steiger 2003).

It is known that VIP mRNA is fairly broadly distributed within the SCN, with the exception of its most rostral or most caudal sections. Short photoperiod exposure inhibited VIP mRNA expression in the SCN of hamsters for at least several hours, and this effect does not require the pineal gland. Thus, the pineal gland may chronically and differentially modulate the expression of VIP mRNA in the SCN where the activity of VIP neurons is decreased after the short photoperiod. Evidence suggest that VIP neurons of the SCN project to the paraventricular nuclei, which is a necessary component of the neural pathway generating the circadian pacemaker, and also modulates the endocrine functions with which these neurons have been associated (Duncan 1998).

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