Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q07644 (polypeptide)
 72,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of neuropeptides to modulate enteric smooth muscle proliferation was examined in primary explant cultures of rabbit gastric antrum and colon smooth muscle. Cell proliferation was determined by [3H]thymidine incorporation measurements and cell counting. Subcultured rabbit antrum and colon myocytes (passages 2-6) preserved a smooth muscle phenotype, as verified by immunohistochemistry for alpha-smooth muscle actin and electron microscopy. Both vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide-(1-38) [PACAP-(1-38)] concentration dependently (10(-10) to 10(-6) M) inhibited the serum-induced [3H]thymidine incorporation [in colon, 48.2 +/- 5.8 and 55.6 +/- 9.3% of control with 10(-6) M VIP and 10(-7) M PACAP-(1-38)] and inhibited increase in cell numbers in cultures derived from the colon but not in those from the antrum. Effects of VIP and PACAP-(1-38) were mimicked by forskolin (10(-7) to 10(-6) M) but not by 8-bromo-cGMP, whereas theophylline enhanced the effects of VIP. Inhibition of nitric oxide synthase with NG-nitro-L-arginine methyl ester (10(-3.5) M) did not alter the effects of VIP. Substance P, motilin, calcitonin gene-related peptide, and somatostatin had no effect. A single class of 125I-labeled VIP binding sites was found in antrum and colon myocyte cultures with an equal affinity for VIP and PACAP-(1-38) [dissociation constant (Kd) in antrum = 3.4 +/- 0.8 nM for VIP and 2.0 +/- 1.0 nM for PACAP-(1-38); Kd in colon = 2.0 +/- 1.0 nM for VIP and 2.8 +/- 1.6 nM for PACAP-(1-38)]. Density of binding sites in the antrum was higher than in the colon. In disease states such as inflammatory bowel disease, inhibition of myocyte proliferation by VIP and PACAP may serve to control smooth muscle hyperplasia in the colon but not in the antrum.
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PMID:Region-specific antiproliferative effect of VIP and PACAP-(1-38) on rabbit enteric smooth muscle. 988 8

Pituitary adenylate cyclase-activating polypeptides (PACAP-27 and -38) are neuropeptides of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family. PACAP receptors are expressed in different brain regions including the cerebellum. We used primary culture of rat cerebellar granule neurons to study the effect of PACAP-38 on apoptosis induced by potassium deprivation. We demonstrated that serum and potassium withdrawal induces a mixture of apoptosis and necrosis rather than apoptosis only. We showed that PACAP-38 increased survival of cerebellar neurons in a dose-dependent manner by specifically decreasing the extent of apoptosis estimated by DNA fragmentation. PACAP-38 induced activation of the extracellular signal-regulated kinase (ERK)-type of MAP kinase through a cAMP-dependent pathway. PD98059, an inhibitor of MEK (MAP kinase kinase), completely abolished the anti-apoptotic effect of PACAP-38, suggesting that MAP kinase pathway activation is necessary for PACAP-38 effect.
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PMID:PACAP-38 protects cerebellar granule cells from apoptosis. 992 2

A receptor for vasoactive-intestinal-peptide (VIP)-related peptides was functionally characterized in a cell line derived from Xenopus melanophores using a recently described microtiter-plate-based bioassay. Activation of the melanophore VIP receptor by VIP or the peptides pituitary-adenylate-cyclase-activating polypeptide (PACAP 38), PACAP 27, and helodermin stimulated intracellular 3'-5' cyclic adenosine monophosphate (cAMP) accumulation and pigment dispersion in the cells. Helodermin, with an EC50 (concentration of peptide inducing half-maximal melanosome dispersion) of 46.5 pM, was the most potent activator of pigment dispersion, followed by PACAP 38 > VIP > PACAP 27. A similar order of potencies was observed for the peptides to induce cAMP accumulation. The responses to VIP agonists were selectively inhibited by the VIP antagonists PACAP-(6-27) and (N-Ac-Tyr(1)-D-Phe2)-growth-hormone-releasing factor[GRF](1-29)-NH2. Taken together, the results suggest that the melanophores express a VIP receptor that shares certain characteristics of, but also differs significantly from, other previously identified VIP receptors.
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PMID:Functional characterization of a receptor for vasoactive-intestinal-peptide-related peptides in cultured dermal melanophores from Xenopus laevis. 1023 Nov 96

PACAP38 and PACAP27, tested at 0.0001-1 microM, potently stimulated synthesis of cyclic AMP in the hypothalamus and cerebral cortex of chicks; the effects of vasoactive intestinal polypeptide (VIP) in the two brain regions were much weaker, reaching statistical significance only at 3 microM concentration. This characteristics suggests the existence in the bird's brain of adenylyl cyclase-linked PAC1 receptors. PACAP27 (0.001-1 microM) concentration-dependently stimulated cyclic AMP production in the hypothalamus and cerebral cortex of three other birds: duck, goose and turkey; the effects were, however, somewhat lower than those in chicks, but comparable to those found in rats. These data demonstrate PACAP to be capable of potently stimulating cyclic AMP generating system in the avian central nervous system.
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PMID:Stimulatory effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on cyclic AMP formation in the hypothalamus and cerebral cortex of four avians and rat. 1038 49

It is well known that psoriasis, an immunogenetic cutaneous disorder whose major pathogenic findings are epidermal hyperplasia and T-cell infiltration, is aggravated by psychological stresses. Although the exact mechanism is not yet clarified, antidromic secretion of neuropeptides by cutaneous nerve fibers is thought to be involved. In this study, we examined the effect and mechanism of vasoactive intestinal polypeptide (VIP), one of the major neuropeptides, on the proliferation of HaCaT cell which is a spontaneous, immortalized, human keratinocyte cell line. Twenty-four and 48 h after its addition, 1 pM to 100 nM of VIP increased the number of cells cultured with/without serum. We indirectly verified VIP(1)R on the surface of HaCaT cell based on the proliferative ability of various VIP families such as VIP, PACAP and secretin, and increased PKA level 30 min after stimulation. However, because H-89, a PKA inhibitor, did not inhibit the proliferative potential of VIP, its mitogenicity is not medicated through VIP(1)R. One nM VIP produced the TGF-alpha protein which is a strong mitogen of keratinocytes and increased in the psoriatic lesion 2.25 times more compared with the control. Genistein, a tyrosine kinase inhibitor, abrogated the mitogenic activity of VIP. Like VIP, VIP fragments, VIP(1-12) and VIP(10-28) also acted as a mitogen for HaCaT cells through the same mechanism. Collectively, our studies clearly show that VIP and its fragments stimulate keratinocyte growth, not through increased cAMP level, but through increased TGF-alpha protein production.
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PMID:Vasoactive intestinal polypeptide stimulates the proliferation of HaCaT cell via TGF-alpha. 1065 22

Vasoactive Intestinal Polypeptide (VIP) interacts with a high affinity to two subclasses of G protein coupled receptors named VPAC(1) and VPAC(2), and has a 3 - 10 fold preference for VPAC(1) over VPAC(2) receptors. Selective ligands for each receptor subclass were recently described. [R(16)]-PACAP (1 - 23) and [L(22)]-VIP are two selective VPAC(1) agonists. Chimaeric human VPAC(2)-VPAC(1) recombinant receptors expressed in CHO cells were used to identify the receptor domains implicated in these two selective ligands recognition. The VPAC(2) preference for [R(16)]-PACAP (1 - 27) over [R(16)]-PACAP (1 - 23) did not require the receptor's NH(2)-terminus domain but involved the whole transmembrane domain. In contrast, the selectivity of [L(22)]-VIP depended only on the presence of the NH(2) terminus and EC(2) domains of the VPAC(1) receptor. The present data support the idea that in the GPCR-B family of receptors the different selective ligands require different domains for their selectivity, and that the peptides carboxyl terminal sequence (amino acids 24 - 27) folds back on the transmembrane receptor domain, close to the peptides, aminoterminus.
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PMID:Characterization of a novel VPAC(1) selective agonist and identification of the receptor domains implicated in the carboxyl-terminal peptide recognition. 1086 88

The effects of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP27 and PACAP38) on isolated parasympathetic neurons of rat intracardiac and submandibular ganglia were examined under voltage clamp using whole-cell patch-clamp recording techniques. VIP and PACAP (</= 10 nM) selectively and reversibly increased the affinity of nicotinic acetylcholine receptor channels (nAChRs) for their agonists resulting in a potentiation of acetylcholine (ACh)-evoked whole-cell currents at low agonist concentrations. VIP-induced potentiation was observed with either ACh or nicotine as the cholinergic agonist. The VIP- but not the PACAP-induced potentiation of ACh-evoked currents was inhibited by [Ac-Tyr1, D-Phe2]-GRF 1-29, amide (100 nM), a selective antagonist of VPAC1 and VPAC2 receptors; whereas the PACAP38- but not the VIP-induced potentiation was inhibited by 100 nM PACAP6-38, a PAC1 and VPAC2 receptor antagonist. The signal transduction pathway mediating VIP- and PACAP-induced potentiation of nicotinic ACh-evoked currents involves a pertussis toxin (PTX)-sensitive G-protein. Intracellular application of 200 microM GTPgammaS or GDPbetaS inhibited VIP-induced potentiation of ACh-evoked whole-cell currents. GTPgammaS alone potentiated ACh- and nicotine-evoked currents and the magnitude of these currents was not further increased by VIP or PACAP. The G-protein subtype modulating the neuronal nAChRs was examined by intracellular dialysis with antibodies directed against alphao, alphai-1,2, alphai-3 or beta G-protein subunits. Only the anti-Galphao and anti-Gbeta antibodies significantly inhibited the effect of VIP and PACAP on ACh-evoked currents. The potentiation of ACh-evoked currents by VIP and PACAP may be mediated by a membrane-delimited signal transduction cascade involving the PTX-sensitive Go protein.
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PMID:VIP and PACAP potentiation of nicotinic ACh-evoked currents in rat parasympathetic neurons is mediated by G-protein activation. 1094 3

To elucidate the functional role of the second extracellular loop of human vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating polypeptide (VIP/PACAP) receptor (hVPAC1R), surface expression, ligand binding, and receptor activation were analyzed. Amino acids in the entire second extracellular loop were individually substituted by alanine by site-directed mutagenesis. The mutant and wild-type receptors were transiently expressed in HEK293 cells and purified cell membranes were tested for the ability to bind VIP, while the receptor activity was measured as potency of cAMP production analysed on intact cells. Surface expression of the substituted conserved residues, W286A, I289A, W294A, and W295A, was evidently decreased to 20-30% compared to the wild-type expression. W286A also showed an significantly reduced potency of cAMP production. Substituted residues as F280A, E281A, and G284A showed a significant reduction in the potency of stimulated cAMP production amounting to 8-46-fold, compared to the wild-type with unaffected surface expression and VIP binding. These results indicate that some residues in the second extracellular loop of the human VPAC1R participate in the active mechanism of a ligand-mediated response without being directly involved in the binding of VIP.
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PMID:Role of second extracellular loop in the function of human vasoactive intestinal polypeptide/pituitary adenylate cyclase activating polypeptide receptor 1 (hVPAC1R). 1098 89

The concentration of pituitary adenylyl cyclase-activating polypeptide [PACAP-(1-38)] in porcine adrenal glands amounted to 14 +/- 3 pmol/g tissue. PACAP immunoreactive (PACAP-IR) fibers innervated adrenal chromaffin cells (often co-localized with choline acetyltransferase). Subcapsular fibers traversed the cortex-innervating endocrine cells and blood vessels [some co-storing mainly calcitonin gene-related peptide but also vasoactive intestinal polypeptide (VIP)]. PACAP-IR fibers were demonstrated in the splanchnic nerves, whereas IR adrenal nerve cell bodies were absent. In isolated, vascularly perfused adrenal gland, splanchnic nerve stimulation (16 Hz) and capsaicin (10(-5) M) increased PACAP-(1-38) release (1.6-fold and 6-fold respectively, P = 0.02). PACAP-(1-38) dose-dependently stimulated cortisol (2 x 10(-10) M; 24-fold increase, P = 0.02) and chromogranin A fragment (2 x 10(-9) M; 15-fold increase, P = 0.05) secretion. Both were strongly inhibited by the PAC(1)/VPAC(2) receptor antagonist PACAP-(6-38) (10(-7) M). PACAP-(6-38) also inhibited splanchnic nerve (10 Hz)-induced cortisol secretion but lacked any effect on splanchnic nerve-induced pancreastatin secretion. PACAP-(1-38) (2 x 10(-10) M) decreased vascular resistance from 5.5 +/- 0.6 to 4.6 +/- 0.4 mmHg. min. ml(-1). PACAP-(6-38) had no effect on this response. We conclude that PACAP-(1-38) may play a role in splanchnic nerve-induced adrenal secretion and in afferent reflex pathways.
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PMID:PACAP-(1-38) as neurotransmitter in the porcine adrenal glands. 1109 31

Maxadilan is a potent vasodilator peptide isolated from salivary gland extracts of the hematophagous sand fly. Recently, the possibility was demonstrated that maxadilan binds to PAC1 receptor (PACAP, pituitary adenylate cyclase activating polypeptide type I receptor) in mammals. In the present study, we demonstrated that: (1) maxadilan specifically binds to PAC1 receptor and stimulates cyclic AMP accumulation in a dose-dependent manner in CHO cells stably expressing PAC1 receptor, not VIP (vasoactive intestinal polypeptide) receptors; that (2) the deleted peptide (amino acid #24-42) of maxadilan (termed max.d.4) also specifically binds to PAC1 receptor although max.d.4 inhibits cyclic AMP accumulation stimulated by both maxadilan and PACAP; and that (3) max.d.4 completely blocks the cyclic AMP accumulation induced by VIP in cultured rat cortical neurons. The expression of specific PACAP receptors in cultured rat cortical neurons was further investigated by the reverse transcription-polymerase chain reaction technique, which showed the presence of mRNA coding for PAC1 receptor among PACAP/VIP family receptors. These data indicate that maxadilan and max.d.4 represent important tools for clarifying the physiological role of PAC1 receptor, and that PAC1 receptor plays an important role in the regulation of the functions induced by PACAP in rat cultured cortical neurons.
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PMID:Maxadilan specifically interacts with PAC1 receptor, which is a dominant form of PACAP/VIP family receptors in cultured rat cortical neurons. 1116 97


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