PACAP 6-38

Inhibitory effect of PACAP(6-38) on relaxations induced by PACAP, VIP and non-adrenergic, non-cholinergic nerve stimulation in the guinea-pig taenia caeci.[Pubmed:10832602]

Naunyn Schmiedebergs Arch Pharmacol. 2000 May;361(5):492-7.

The effect of the pituitary adenylate cyclase activating polypeptide (PACAP) receptor antagonist PACAP(6-38) on the relaxant response to exogenous PACAP, vasoactive intestinal polypeptide (VIP) and nonadrenergic, non-cholinergic (NANC) nerve stimulation was tested in the guinea-pig taenia caeci, in the presence of atropine (10(-6) M) and guanethidine (3x10(-6) M). PACAP(6-38) (3x10(-6) M) strongly inhibited sub-maximal relaxations evoked by exogenous PACAP (1-3x 10(-8) M) or VIP (10(-8) M), but not those due to isoprenaline (4-8x10(-8) M) or ATP (10(-6) M). PACAP(6-38) caused a small but significant (approximately 20%) inhibition of the NANC relaxation due to electrical field stimulation (1 Hz or 10 Hz for 20 s). At these frequencies PACAP(6-38) caused no inhibition of the NANC relaxation in the presence of the P2 purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 5x10(-5) M), or PPADS plus the NO-synthase blocker NG-nitro-L-arginine (L-NOARG; 10(-4) M); in preparations pretreated with L-NOARG (10(-4) M) alone PACAP(6-38) retained its inhibitory effect. The PPADS- and L-NOARG-resistant NANC relaxation with 10 Hz electrical stimulation was blocked by apamin (10(-7) M); it was not significantly modified by the tachykinin receptor antagonist spantide (10(-5) M). Tachyphylaxis to PACAP(1-27) (10(-7) M for 10 min) strongly inhibited the relaxation due to PACAP(1-38) (1-3x10(-8) M) and reduced electrical stimulation-evoked relaxations by half. The putative VIP antagonist VIP(10-28) (10(-5) M) failed to significantly reduce the relaxant action of exogenous VIP (1-3x10(-8) M). Relaxation induced by PACAP(1-38) (1-2x10(-8) M) was not influenced by a mixture of PPADS (5x10(-5) M) and L-NOARG (10(-4) M). It is concluded that: (a) PACAP(6-38) is a VIP/PACAP antagonist in the guinea-pig taenia caeci; (b) a release of a VIP/PACAP-like substance from enteric nerves is involved in the NANC relaxation in this preparation, but its contribution is relatively small and seems to depend on the functional integrity of the PPADS-sensitive inhibitory mechanism; (c) the PPADS- plus L-NOARG-resistant NANC relaxation probably involves apamin-sensitive K+ channels.

PACAP-(6-38) inhibits the effects of vasoactive intestinal polypeptide, but not PACAP, on the small intestinal circular muscle.[Pubmed:11728434]

Eur J Pharmacol. 2001 Nov 16;431(2):259-64.

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide-(1-38) (PACAP) have been found to stimulate distension-induced peristaltic motility in the guinea-pig isolated small intestine. In this study, we tested whether the putative VIP/PACAP receptor antagonist PACAP-(6-38) counteracts the properistaltic effect of VIP and PACAP in isolated segments of the guinea-pig small intestine. VIP (100 nM) and PACAP (30 nM) had a stimulatory effect, i.e., lowered the peristaltic pressure threshold at which peristaltic waves were triggered and enhanced the frequency of peristaltic waves. PACAP-(6-38) (3 microM) was per se without effect on peristalsis but prevented or reversed the peristaltic motor stimulation caused by VIP, when it was given before or after the agonist, respectively. PACAP-(6-38), however, failed to antagonize the properistaltic effect of PACAP. In ileal circular strips treated with tetrodotoxin (1 microM) and indomethacin (3 microM), spontaneous myogenic activity was inhibited by VIP (5-30 nM). This effect was significantly reduced by a pretreatment with PACAP-(6-38) (3 microM). A similar inhibition by PACAP-(1-38) (10-500 nM) was not influenced by the antagonist. It is concluded that PACAP-(6-38) is a VIP receptor antagonist, both in the peristaltic motor pathways and at the level of the circular muscle of the guinea-pig small intestine. The lack of a motor effect of PACAP-(6-38) on its own indicates that VIP acting on PACAP-(6-38)-sensitive receptors (located on neurons and/or the smooth muscle) is unlikely to participate in peristaltic motor regulation.

CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6-38 as a CART receptor antagonist.[Pubmed:21855138]

Neuropeptides. 2011 Oct;45(5):351-8.

CART peptides are peptide neurotransmitters and hormones that are involved in many different physiological responses. While much is known about the peptides regarding their structure, processing and gene regulation, less is known about their postsynaptic actions and receptors. Using (125)I-CART 61-102 as a ligand and unlabeled CART 61-102 or CART 55-102 as displacers, high-affinity specific binding was detected in PC12 cells. Differentiation of the PC12 cells increased specific binding several-fold. The increase in specific binding found after differentiation was inhibited by actinomycin D and cycloheximide, suggesting that the increase in specific binding was dependent on RNA and protein synthesis. CART 1-27, a peptide that has never been shown to elicit responses, did not displace (125)I-CART 61-102 binding, nor did more than 20 other peptides that were examined. Surprisingly, however, PACAP 1-38 and PACAP 6-38 were found to be low-affinity inhibitors of CART binding. CART treatment increased binding of (35)S-GTPgamma-S to PC12 cell membranes. Moreover, CART treatment of intact PC12 cells elicited robust increases in phospho-ERK in a manner that was increased with differentiation, blocked by pertussis toxin and antagonized by PACAP 6-38. These findings extend previous research and suggest that the CART binding site in PC12 cells reflects a G protein-coupled receptor linked with Gi/o, and also demonstrate that PACAP 6-38 may be useful as a CART receptor antagonist.

Intravesical PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice.[Pubmed:27146136]

J Mol Neurosci. 2016 Jun;59(2):290-9.

Chronic NGF overexpression (OE) in the urothelium, achieved through the use of a highly urothelium-specific uroplakin II promoter, stimulates neuronal sprouting in the urinary bladder, produces increased voiding frequency and non-voiding contractions, and referred somatic sensitivity. Additional NGF-mediated pleiotropic changes might contribute to increased voiding frequency and pelvic hypersensitivity in NGF-OE mice such as neuropeptide/receptor systems including PACAP(Adcyap1) and PAC1 receptor (Adcyap1r1). Given the presence of PAC1-immunoreactive fibers and the expression of PAC1 receptor expression in bladder tissues, and PACAP-facilitated detrusor contraction, whether PACAP/receptor signaling contributes to increased voiding frequency and somatic sensitivity was evaluated in NGF-OE mice. Intravesical administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p

The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein.[Pubmed:16401644]

FASEB J. 2006 Mar;20(3):512-4.

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has neurotrophic as well as anti-apoptotic properties and is involved in learning and memory processes. Its specific G protein-coupled receptor PAC1 is expressed in several central nervous system (CNS) regions, including the hippocampal formation. Here we examined the effect of PAC1 receptor activation on alpha-secretase cleavage of the amyloid precursor protein (APP) and the production of secreted APP (APPsalpha). Stimulation of endogenously expressed PAC1 receptors with PACAP in human neuroblastoma cells increased APPsalpha secretion, which was completely inhibited by the PAC1 receptor specific antagonist PACAP-(6-38). In HEK cells stably overexpressing functional PAC1 receptors, PACAP-27 and PACAP-38 strongly stimulated alpha-secretase cleavage of APP. The PACAP-induced APPsalpha production was dose dependent and saturable. This increase of alpha-secretase activity was completely abolished by hydroxamate-based metalloproteinase inhibitors, including a preferential ADAM 10 inhibitor. By using several specific protein kinase inhibitors, we show that the MAP-kinase pathway [including extracellular-regulated kinase (ERK) 1 and ERK2] and phosphatidylinositol 3-kinase mediate the PACAP-induced alpha-secretase activation. Our findings provide evidence for a role of the neuropeptide PACAP in stimulation of the nonamyloidogenic pathway, which might be related to its neuroprotective properties.

PACAP(6-38) inhibits the growth of prostate cancer cells.[Pubmed:9566707]

Cancer Lett. 1998 Mar 13;125(1-2):131-9.

The effects of pituitary adenylyl cyclase activating polypeptide (PACAP) analogs on prostate cancer cell lines was investigated. 125I-PACAP-27 bound with high affinity to PC-3 cells (Kd = 10 nM) to a single class of sites (Bmax = 30000/cell). By RT-PCR, a major 305 bp band was observed using cDNA derived from PC-3, LNCaP or DU-145 cells. Specific 125I-PACAP binding was inhibited with high affinity by PACAP-27, PACAP-38 and PACAP(6-38) (IC50 values of 15, 10 and 300 nM, respectively) but not by PACAP(28-38). PACAP elevated cAMP and the increase caused by PACAP-27 was reversed by PACAP(6-38). PACAP transiently increased c-fos gene expression and the increase in c-fos mRNA was reversed by PACAP(6-38). PACAP-27 stimulated colony formation in PC-3 cells, whereas PACAP(6-38) reduced colony number and size. In nude mice bearing PC-3 xenografts, PACAP(6-38) significantly slowed tumor growth. These data suggest that biologically active type 1 PACAP receptors are present on human prostate cancer cells and that prostate cancer cell growth is inhibited by PACAP(6-38).

Structural requirements for the occupancy of pituitary adenylate-cyclase-activating-peptide (PACAP) receptors and adenylate cyclase activation in human neuroblastoma NB-OK-1 cell membranes. Discovery of PACAP(6-38) as a potent antagonist.[Pubmed:1321043]

Eur J Biochem. 1992 Jul 1;207(1):239-46.

In these structure activity studies, the 46 analogs of the 27-amino-acid form of the pituitary-adenylate-cyclase-activating peptide, PACAP(1-27), and the 38-amino-acid form, PACAP(1-38), were either monosubstituted or bisubstituted at positions 1-3, 20 and 21 or N-terminally shortened. All analogs were compared on human neuroblastoma NB-OK-1 cell membranes for their ability to occupy 125I-[AcHis1]PACAP(1-27)-labelled receptors (AcHis, N alpha-acetylhistidine) and to activate adenylate cyclase (in terms of potency and intrinsic activity). The monophasic slope of dose/effect curves on both parameters suggested interaction with one class of PACAP receptor. Residues 28-38 in the C-terminally extended peptide, PACAP(1-38), played a favorable role in recognition, in that receptors coupled to adenylate cyclase were, in general, more sensitive to PACAP(1-38) analogs than to the corresponding PACAP(1-27) analogs. At variance with PACAP(6-27), PACAP(6-38) was well recognized and acted as a potent competitive antagonist (Ki 1.5 nM). Residues 1-3 were all important in enzyme activation: modification of the beta-turn potential gave full agonists (the LAla2 and DAla2 derivatives) or partial agonists (LPhe2 and DPhe2; LArg2 and DArg2; Glu3 and Asn3). Finally, a proper alpha-helix was also important: the combined substitution of Lys21/Lys22 by Gly21/Gly22 decreased the binding affinity sharply.

PACAP (6-38), human, ovine, rat is a potent PACAP receptor antagonist with IC50s of 30, 600, and 40 nM for PACAP type I receptor, PACAP type II receptor VIP1, and PACAP type II receptor VIP2, respectively.

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