Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PACAP receptor (PACAP I receptor, selective for PACAP) and the PACAP II VIP1 receptor (recognizing PACAP and VIP with the same high affinity) were stably expressed in Chinese Hamster Ovary (CHO) cells. Cell lines expressing different receptor densities, as measured by binding saturation curves, were selected. Inositol phosphate production was stimulated dose dependently in all the cell lines by PACAP and VIP, and the order of potency of the agonists was identical to that of high affinity receptor occupancy. The stimulatory effect of a saturating peptide concentration was proportional to the total receptor density. At similar receptor densities, however, the PACAP receptor mediated stimulation was higher than the VIP receptor-mediated stimulation. Pretreatment of the cells with pertussis toxin for 8 h had no effect on receptor densities, did not alter the PACAP stimulated inositol phosphate synthesis by the cells expressing the PACAP I receptor but markedly inhibited the response of the cells expressing the PACAP II VIP1 receptor. Thus, the present results indicate that the two G(s)-coupled PACAP I and PACAP II VIP1 receptors may stimulate IP production. The maximal stimulation depended on the number of receptor expressed; the PACAP I and PACAP II VIP1 receptors probably activated the phospholipase C through G proteins of the G(q), and of the G(i)/G(o) families, respectively.
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PMID:The pituitary adenylate cyclase activating polypeptide (PACAP I) and VIP (PACAP II VIP1) receptors stimulate inositol phosphate synthesis in transfected CHO cells through interaction with different G proteins. 922 29

Pituitary adenylate cyclase activating polypeptide-27 (PACAP-27) caused a dose-dependent increase in met-enkephalin secretion and increased production of met-enkephalin peptide and proenkephalin A (PEnk) mRNA in bovine chromaffin cells, at concentrations as low as 300 pM. PACAP-38 was less potent than PACAP-27, but had similar effects. Vasoactive intestinal polypeptide (VIP) (1-100 nM) was without appreciable effect on either enkephalin secretion or biosynthesis, implicating PACAP type I receptors in PACAP-stimulated enkephalin secretion and synthesis. PACAP type I receptors can activate adenylate cyclase and stimulate phospholipase C through heterotrimeric G protein interactions, leading to increased intracellular cyclic AMP (cAMP), inositol triphosphate (IP3)-mediated calcium mobilization, and calcium- and diacylglycerol (DAG)-mediated protein kinase C (PKC) activation. Enkephalin secretion evoked by 10-100 nM PACAP-27 was not inhibited by 1 microM (-)-202-791, an L-type specific dihydropyridine calcium channel blocker, but was inhibited 65-80% by the arylalkylamine calcium channel blocker D600. Forty mM potassium-evoked secretion was inhibited > 90% by both D600 and (-)-202-791, 25 microM forskolin-induced secretion was blocked < 50% by D600 and was unaffected by (-)-202-791, and 100 nM phorbol myristate acetate (PMA)-induced secretion was unaffected by either D600 or (-)-202-791. Enkephalin biosynthesis was increased by 10 nM PACAP-27, as measured by increased met-enkephalin pentapeptide content and PEnk A mRNA levels. PACAP-, forskolin-, and PMA-stimulated enkephalin synthesis were not blocked by D600 or (-)-202-791. Elevated potassium-induced enkephalin biosynthesis upregulation was completely blocked by either D600 or (-)-202-791 at the same concentrations. PACAP acting through type I PACAP receptors couples calcium influx-dependent enkephalin secretion and calcium influx-independent enkephalin biosynthesis in chromaffin cells. Restriction of the effects of enhanced calcium influx to stimulation of secretion, but not of biosynthesis, is unique to PACAP. By contrast, potassium-induced enkephalin biosynthesis upregulation is completely calcium influx dependent, specifically via calcium influx through L-type calcium channels. We propose that subpopulations of voltage-dependent calcium channels are differentially linked to intracellular signal transduction pathways that control neuropeptide gene expression and secretion in chromaffin cells.
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PMID:PACAP activates calcium influx-dependent and -independent pathways to couple met-enkephalin secretion and biosynthesis in chromaffin cells. 982 85

We have recently shown that the two bioactive forms of pituitary adenylate cyclase-activating polypeptide, PACAP38 and PACAP27, stimulate GH release and GH messenger RNA (mRNA) accumulation in cultured porcine pituitary cells. However, dose- and time-related differences in the response to both peptides suggested that the signaling mechanisms activated by PACAP38 and PACAP27 in this cell type could differ. To test this hypothesis, we have evaluated hormone release and GH mRNA content after PACAP treatment in combination with selective activators and inhibitors of the adenylate cyclase/cAMP/protein kinase A and the phospholipase C/inositol phosphate (IP)/protein kinase C pathways, and with blockers of intra- and extracellular Ca2+. Our results show that activation of the adenylate cyclase/cAMP/protein kinase A system, and extracellular Ca2+ entry through L-type Ca2+-channels are prevailing and requisite signals for the transduction of the stimulatory effects of both PACAP38 and PACAP27 on GH release and transcription in porcine somatotropes. However, phospholipase C and intracellular Ca2+ also contribute, although partially, to PACAP38-induced, but not to PACAP27-induced increase in porcine GH secretion and mRNA levels. These findings demonstrate that in normal somatotropes, PACAP38 can activate multiple transduction pathways that differ from those employed by PACAP27. Moreover, these differences could account for the previously described divergences in the actions of either peptide in porcine somatotropes.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and PACAP27 activate common and distinct intracellular signaling pathways to stimulate growth hormone secretion from porcine somatotropes. 983 51

In this study, the secretory effects of PACAP and PACAP analogues on [3H]serotonin-loaded purified rat peritoneal mast cells (RPMCs) were investigated. PACAP(1-27) and PACAP(6-27) stimulated [3H]serotonin release with low potency (ED50: 2 x 10(-6) M) but high efficacy. The N-terminally truncated PACAP form, PACAP(6-27), stimulated tracer release with an ED50 of 0.2 x 10(-6) M, indicating a high-affinity PACAP receptor-independent mechanism of action. The secretory response to PACAP(1-27) could be inhibited by 60-min preincubation with pertussis toxin (ptx), which inhibits G proteins. U73122, a cell-permeable phospholipase C inhibitor, dose-dependently inhibited the secretory effect of 5 microM PACAP(1-27) with an IC50 value of 4 microM (N = 4; p < 0.006). We conclude that PACAP exerts a secretory effect in RPMCs by high-affinity PACAP receptor-independent direct activation of one or more G proteins, which may then activate the PLC-dependent signal-transduction pathway.
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PMID:Pituitary adenylate cyclase activating polypeptide induces degranulation of rat peritoneal mast cells via high-affinity PACAP receptor-independent activation of G proteins. 992 6

We have compared the effects of pituitary adenylate cyclase-activating polypeptide (PACAP-27) on the five main cell types of rat anterior pituitary in primary culture by monitoring changes in cytosolic Ca2+ concentration ([Ca2+]i) in single fura-2-loaded cells. Cells were typed by multiple sequential primary immunocytochemistry at the end of the Ca2+ measurements. PACAP-27 increased [Ca2+]i by three different mechanisms, each one dominant in a given cell type. These involved Ca2+ entry or release from the stores and mediation through different second messenger pathways: (1) stimulation of Ca2+ entry mediated by cAMP was the main mechanism in somatotrophs; (2) Ca2+ release from the intracellular Ca2+ stores mediated by phospholipase C (PLC) was the dominant modality in gonadotrophs; (3) stimulation of Ca2+ entry not mediated by cAMP was the main mechanism in lactotrophs. A minor fraction of somatotrophs (11%) may also use mechanism 3. Corticotrophs and thyrotrophs exhibited weak responses to PACAP (<10% of the cells responded), which in all cases were mediated by mechanism 1. Mechanism 3 represents a novel effect of PACAP which cannot be explained by interaction with the conventional PACAP receptor families.
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PMID:Differential calcium responses to the pituitary adenylate cyclase-activating polypeptide (PACAP) in the five main cell types of rat anterior pituitary. 1100 7

Activation of protease-activated receptor-1 (PAR-1) produces a dual action, apamin-sensitive relaxation followed by contraction, in the rat duodenal smooth muscle, which is partially dependent on activation of L-type Ca2+ channels, protein kinase C (PKC) or tyrosine kinase (TK), and resistant to tetrodotoxin. The present study further characterized the PAR-1-mediated duodenal responses. Removal of extracellular Ca2+ as well as SK&F96365 reduced the contraction due to the PAR-1 agonist TFLLR-NH2 (TFp-NH2) by 60-80% that was similar to the extent of the inhibition by nifedipine. Lowering of the extracellular Na+ concentration, but not IAA-94, a Cl- channel inhibitor, reduced both the PAR-1-mediated contraction and relaxation by about 50%. U73122, a phospholipase C (PLC) inhibitor, or wortmannin, a phosphatidyl inositol 3'-kinase (PI3K) inhibitor, significantly reduced the PAR-1-mediated contraction, but not the relaxation, by itself, as the PKC inhibitor GF109203X and the TK inhibitor genistein did. U73122 or wortmannin, like GF109203X, when applied in combination with genistein, significantly reduced the PAR-1-mediated relaxation. The relaxation was resistant to antagonists of PACAP receptors, VIP receptors and P2 purinoceptors. Thus, the PAR-1-mediated contraction is considered to be dependent on intracellular and extracellular Ca2+, the influx of the latter being induced through activation of L-type Ca2+ channels triggered by the enhanced Na+ permeability, and that PLC and PI3K, in addition to PKC and TK, are involved in the PAR-1-mediated dual responses. Furthermore, non-adrenergic, non-cholinergic nerve neurotransmitter candidates that may modulate K+ channels do not appear to contribute to the relaxation by PAR-1 activation.
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PMID:Characterization of the protease-activated receptor-1-mediated contraction and relaxation in the rat duodenal smooth muscle. 1106 74

Morphological studies identified PACAP-immunoreactive nerve fibers in dense pericellular arrangements around virtually every cholinergic parasympathetic neuron of guinea pig cardiac ganglia; all postganglionic cardiac neurons expressed membrane-associated PAC1 receptor protein. Characterization of the alternative splice variants established predominant expression of the PAC1(very short) receptor transcript containing neither HIP nor HOP exons. PACAP depolarized cardiac neurons and increased membrane excitability; the excitability resulted from neither altered action potential properties nor inhibition of IM. Treatment of cardiac ganglia explants with PACAP significantly reduced the numbers of cholinergic neurons coexpressing somatostatin immunoreactivity, which did not appear to be correlated with prosomatostatin mRNA expression. The PACAP-mediated decrease in somatostatin immunoreactive neurons required calcium influx through L-type calcium channels and activation of adenylyl cyclase, whereas activation of phospholipase C or protein kinase A was not required. These observations indicate that PACAP through the PAC1 receptors elicits complex actions on guinea pig parasympathetic cardiac ganglia neurons, including modulation of membrane ion conductances and modulation of neuropeptide expression.
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PMID:PACAP peptides modulate guinea pig cardiac neuron membrane excitability and neuropeptide expression. 1119 24

We have previously shown that PACAP stimulates in vitro the secretion of corticosteroids by frog adrenal explants and that PACAP increases cAMP formation and cytosolic calcium concentration ('Ca2+'i) in adrenocortical cells. The aim of the present study was to investigate the involvement of cAMP and 'Ca2+'i in the stimulatory effect of PACAP on steroid production. Incubation of adrenal explants with PACAP resulted in a significant increase in total inositol phosphate formation. Administration of the protein kinase A inhibitor, H89, markedly reduced the stimulatory effect of PACAP on corticosterone and aldosterone secretion by perifused adrenal slices. In contrast, chelation of intracellular or extracellular calcium, or incubation with calcium channel blockers, had no effect on PACAP-evoked steroid secretion. Incubation of the cells with BAPTA or thapsigargin totally suppressed the stimulatory effect of PACAP on 'Ca2+'i. In contrast, suppression of extracellular calcium with EGTA or blockage of voltage-dependent Ca2+ channels did not impair PACAP-induced Ca2+ response. These data indicate that, in frog adrenocortical cells, the stimulatory effect of PACAP on steroid secretion is mediated through activation of the cAMP/PKA pathway. Concurrently, PACAP causes calcium mobilization from IP(3)-dependent intracellular stores through activation of a phospholipase C, while the calcium response is not involved in the stimulatory effect of PACAP on corticosteroid secretion.
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PMID:Involvement of the adenylyl cyclase/protein kinase A signaling pathway in the stimulatory effect of PACAP on frog adrenocortical cells. 1688 5

PACAP and its receptors are expressed in growth zones of the brain. By stimulating PAC(1)-receptors PACAP can enhance, as well as reduce, the proliferation rate in a cell-type dependent manner. PACAP can enhance the proliferation rate by activating phospholipase C and protein kinase C, although other signal transduction pathways may also be responsible. PACAP can suppress proliferation by inhibiting protein complexes of the cyclins D and E with the cyclin-dependent kinases 4/6 and 2, respectively, which are necessary for entry into the cell cycle. PACAP seems to exert these inhibitory effects by acting via the Sonic hedgehog glycoprotein and the small GTPase RhoA. Also, the activation of a cyclin-dependent kinase inhibitor has been suggested. The signal transduction pathways mediating the effects of PACAP on proliferation are discussed.
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PMID:The effects of PACAP on neural cell proliferation. 1701 42

VIP and PACAP are pleiotropic peptides belonging to the secretin superfamily of brain-gut peptides and interact specifically with three receptors (VPAC(1), PAC(1) and VPAC(2)) from the class II B G protein-coupled receptor family. There is immense interest regarding their molecular evolution which is often described closely alongside gene and/or genome duplications. Despite the wide array of information available in various vertebrates and one invertebrate the tunicate, their evolutionary origins remain unresolved. Through searches of genome databases and molecular cloning techniques, the first lamprey VIP/PACAP ligands and VPAC receptors are identified from the Japanese lamprey. In addition, two VPAC receptors (VPACa/b) are identified from inshore hagfish and ligands predicted for sea lamprey. Phylogenetic analyses group these molecules into their respective PHI/VIP, PRP/PACAP and VPAC receptor families and show they resemble ancestral forms. Japanese lamprey VIP/PACAP peptides synthesized were tested with the hagfish VPAC receptors. hfVPACa transduces signal via both adenylyl cylase and phospholipase C pathways, whilst hfVPACb was only able to transduce through the calcium pathway. In contrast to the widespread distribution of VIP/PACAP ligands and receptors in many species, the agnathan PACAP and VPAC receptors were found almost exclusively in the brain. In situ hybridisation further showed their abundance throughout the brain. The range of VIP/PACAP ligands and receptors found are highly useful, providing a glimpse into the evolutionary events both at the structural and functional levels. Though representative of ancestral forms, the VIP/PACAP ligands in particular have retained high sequence conservation indicating the importance of their functions even early in vertebrate evolution. During these nascent stages, only two VPAC receptors are likely responsible for eliciting functions before evolving later into specific subtypes post-Agnatha. We also propose VIP and PACAP's first functions to predominate in the brain, evolving alongside the central nervous system, subsequently establishing peripheral functions.
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PMID:Agnathan VIP, PACAP and their receptors: ancestral origins of today's highly diversified forms. 2295


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