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)

Pituitary adenylate cyclase-activating polypeptides (PACAP) have potent regulatory and neurotrophic activities on superior cervical ganglion (SCG) sympathetic neurons with pharmacological profiles consistent for the PACAP-selective PAC(1) receptor. Multiple PAC(1) receptor isoforms are suggested to determine differential peptide potency and receptor coupling to multiple intracellular signaling pathways. The current studies examined rat SCG PAC(1) receptor splice variant expression and coupling to intracellular signaling pathways mediating PACAP-stimulated peptide release. PAC(1) receptor mRNA was localized in over 90% of SCG neurons, which correlated with the cells expressing receptor protein. The neurons expressed the PAC(1)(short)HOP1 receptor but not VIP/PACAP-nonselective VPAC(1) receptors; low VPAC(2) receptor mRNA levels were restricted to ganglionic nonneuronal cells. PACAP27 and PACAP38 potently and efficaciously stimulated both cAMP and inositol phosphate production; inhibition of phospholipase C augmented PACAP-stimulated cAMP production, but inhibition of adenylyl cyclase did not alter stimulated inositol phosphate production. Phospholipase C inhibition blunted neuron peptide release, suggesting that the phosphatidylinositol pathway was a prominent component of the secretory response. These studies demonstrate preferential sympathetic neuron expression of PACAP-selective receptor variants contributing to regulation of autonomic function.
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PMID:Pituitary adenylate cyclase-activating polypeptides directly stimulate sympathetic neuron neuropeptide Y release through PAC(1) receptor isoform activation of specific intracellular signaling pathways. 1048 12

The direct effects of pituitary adenylate cyclase-activating polypeptides (PACAP) on sympathetic neurons were investigated using rat superior cervical ganglion neurons. Electrophysiological and pharmacological analyses were used to evaluate PACAP modulation of sympathetic neuron membrane potentials and to investigate potential ionic and intracellular signaling mechanisms mediating the responses. More than 90% of the sympathetic neurons were depolarized by the PACAP peptides even when stimulated release was blocked, indicating that the PACAP peptides elicited primary responses in the postganglionic neurons. The response profile was consistent for activation of PACAP-selective PAC(1) receptors: nanomolar concentrations of PACAP27 and PACAP38 were required to stimulate depolarization, whereas vasoactive intestinal peptide failed to evoke any response. Furthermore, depolarizations elicited by PACAP27 were reduced by the PAC(1) receptor antagonist PACAP(6-38). Both sodium influx and inhibition of a potassium current contributed to the peptide-induced depolarizations. Activation of neither pertussis toxin- nor cholera toxin-sensitive G-proteins was required for generation of the depolarizations. cAMP and diacylglycerol production and activation of protein kinase A or protein kinase C also were not requisite for the responses. By contrast, phospholipase C (PLC)-dependent inositol 1,4,5-triphosphate (IP(3)) synthesis was crucial to the PACAP-mediated depolarizations. Although calcium release from IP(3)-sensitive stores was not required for the PACAP-induced responses, inhibition of IP(3) receptors reduced the depolarizations. Thus, among the many signal transduction pathways coupled to the PAC(1) receptor, the PACAP-induced depolarization of sympathetic neurons appears to require activation of PLC and subsequent generation of IP(3).
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PMID:Mechanisms mediating pituitary adenylate cyclase-activating polypeptide depolarization of rat sympathetic neurons. 1100 93

The VPAC(1) and VPAC(2) receptors for vasoactive intestinal polypeptide and the PAC(1) receptor for pituitary adenylate cyclase-activating polypeptide are members of a subfamily of G protein-coupled receptors (GPCRs). We recently reported that phospholipase D (PLD) activation by members of the rhodopsin group of GPCRs occurs by at least two routes, one of which seems to involve the small G protein ADP-ribosylation factor (ARF) and its physical association with GPCRs. Here we report that rat VPAC and PAC(1) receptors can also stimulate PLD (albeit less potently than adenylate cyclase) in transfected cells and also in cells where they are natively expressed. PLD responses of the VPAC receptors and the hop1 spice variant of the PAC(1) receptor but not its null form are sensitive to brefeldin A (BFA), an inhibitor of GTP exchange at ARF. The presence of the hop1 cassette in the rat PAC(1) receptor facilitates PLD activation in the absence of marked changes in ligand binding, receptor internalization, and adenylate cyclase activation, with some reduction in phospholipase C activation. Both VPAC(2) and PAC(1-hop1) (but not PAC(1-null)) receptors were shown to associate with immunoprecipitates directed against native or epitope-tagged ARF. A chimeric construct of the VPAC(2) receptor body with intracellular loop 3 (i3) of the PAC(1-null) receptor mediated BFA-insensitive activation of PLD, whereas the response of the corresponding PAC(1-hop1) construct was BFA-sensitive. Motifs in i3 of the PAC(1-hop1) receptor may act as critical determinants of coupling to ARF-dependent PLD activation by contributing to the GPCR:ARF interface.
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PMID:ADP-ribosylation factor-dependent phospholipase D activation by VPAC receptors and a PAC(1) receptor splice variant. 1135 14

This study has demonstrated that the short and long form of the pituitary adenylate cyclase-activating polypeptide (PACAP), i.e. PACAP(27) and PACAP(38), moderately but significantly, and in a concentration (0.5-5 microM)-dependent manner, stimulated inositol phosphates (IPs) accumulation in myo-[(3)H]inositol-prelabeled cerebral cortical and hypothalamal slices of chick and duck, and in slices of rat cerebral cortex; both peptides had no effect on IPs formation in rat hypothalamus. Vasoactive intestinal peptide (VIP; 0.5-5 microM) weakly enhanced IPs accumulation in chick hypothalamus, had no significant action in chick cerebral cortex (in fact there was a tendency to attenuate the IPs response in this tissue), and slightly, but significantly, inhibited the IPs accumulation in rat cerebral cortex. VIP showed no activity in rat hypothalamus. It is concluded that the stimulatory action of PACAP on phosphoinositide metabolism in avian cerebral cortex, similar to rat cerebral cortex, is mediated via phospholipase C-linked PAC(1) type receptors. In chick hypothalamus, however, there may be a component of VPAC type receptors stimulating IPs formation.
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PMID:Stimulatory effects of pituitary adenylate cyclase-activating polypeptide on inositol phosphates accumulation in avian cerebral cortex and hypothalamus. 1195 14

The PAC(1), VPAC(1) and VPAC(2) receptors are members of the secretin (Group II) family of G protein-coupled receptors. All members of this family activate adenylate cyclase and several have also been shown to activate phospholipase C. We have recently reported that the rat VPAC(1), VPAC(2) and PAC(1) receptors activate phospholipase D and that distinct pathways are utilised by two intracellular loop 3 splice variants of PAC(1), one of which is ARF-dependent. Phospholipase D activation by the hop1, but not the null (short), form of the PAC(1) receptor is sensitive to brefeldin A, an inhibitor of GTP exchange at ARF. We have expressed the null and hop1 intracellular loop 3 domains of the human PAC(1) receptor in bacteria as GST-fusion proteins and used them as peptide affinity matrices to determine whether a functional interaction exists between these domains and ARF. Using this GST pull-down assay, we have shown binding of the small G protein ARF6 to the hop1 but not the null domain of this receptor.
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PMID:Specific interaction between the hop1 intracellular loop 3 domain of the human PAC(1) receptor and ARF. 1240 33

To understand the role of growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP) and to examine the functional significance of the co-expression of GHRH and PACAP in fish, their receptors were characterized in zebrafish. Three cDNAs encoding the PAC(1) receptor, the VPAC(1) receptor, and the partial GHRH receptor were identified from zebrafish. Functional expression of the PAC(1) and VPAC(1) receptors revealed that both are potently coupled to the adenylyl cyclase pathway, but only the PAC(1) receptor is coupled to the phospholipase C pathway. Transcripts for all three receptors were widely distributed, often in an overlapping pattern in the adult zebrafish. Also, one splice variant of the partial GHRH receptor and three splice variants of the PAC(1) receptor were identified from adult zebrafish. The long GHRH receptor transcript contained a 27 amino acid insert in transmembrane domain 5 encoding a premature stop codon leading to a truncated receptor protein. For the PAC(1) receptor, two of the splice variants corresponded to the hop1 and hop2 variants characterized in mammals. The third splice variant identified from the gill encoded a novel 107 bp insert containing a premature stop codon. Therefore, PACAP and GHRH have widespread, overlapping target sites suggesting a coordinated role for these hormones in evolution.
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PMID:Characterization of four receptor cDNAs: PAC1, VPAC1, a novel PAC1 and a partial GHRH in zebrafish. 1571 35

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are the main endogenous ligands of a class of G protein-coupled receptors (Rs). Three subtypes of PACAP/VIP Rs have been identified and named PAC(1)-Rs, VPAC(1)-Rs, and VPAC(2)-Rs. The PAC(1)-R almost exclusively binds PACAP, while the other two subtypes bind with about equal efficiency VIP and PACAP. VIP, PACAP, and their receptors are widely distributed in the body tissues, including the adrenal gland. VIP and PACAP are synthesized in adrenomedullary chromaffin cells, and are released in the adrenal cortex and medulla by VIPergic and PACAPergic nerve fibers. PAC(1)-Rs are almost exclusively present in the adrenal medulla, while VPAC(1)-Rs and VPAC(2)-Rs are expressed in both the adrenal cortex and medulla. Evidence indicates that VIP and PACAP, acting via VPAC(1)-Rs and VPAC(2)-Rs coupled to adenylate cyclase (AC)- and phospholipase C (PLC)-dependent cascades, stimulate aldosterone secretion from zona glomerulosa (ZG) cells. There is also proof that they can also enhance aldosterone secretion indirectly, by eliciting the release from medullary chromaffin cells of catecholamines and adrenocorticotropic hormone (ACTH), which in turn may act on the cortical cells in a paracrine manner. The involvement of VIP and PACAP in the regulation of glucocorticoid secretion from inner adrenocortical cells is doubtful and surely of minor relevance. VIP and PACAP stimulate the synthesis and release of adrenomedullary catecholamines, and all three subtypes of PACAP/VIP Rs mediate this effect, PAC(1)-Rs being coupled to AC, VPAC(1)-Rs to both AC and PLC, and VPAC(2)-Rs only to PLC. A privotal role in the catecholamine secretagogue action of VIP and PACAP is played by Ca(2+). VIP and PACAP may also modulate the growth of the adrenal cortex and medulla. The concentrations attained by VIP and PACAP in the blood rule out the possibility that they act as true circulating hormones. Conversely, their adrenal content is consistent with a local autocrine-paracrine mechanism of action.
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PMID:Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland. 1669 81

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

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul

In the goldfish pituitary, nerve fibers containing pituitary adenylate cyclase-activating polypeptide (PACAP) are located in close proximity to somatolactin (SL)-producing cells, and PACAP enhances SL release from cultured pituitary cells. However, there is little information about the mechanism of PACAP-induced SL release. In order to elucidate this issue, we used the cell immunoblot method. Treatment with PACAP at 10(-8) and 10(-7)M, but not with vasoactive intestinal polypeptide (VIP) at the same concentrations, increased the immunoblot area for SL-like immunoreactivity from dispersed pituitary cells, and PACAP-induced SL release was blocked by treatment with the PACAP selective receptor (PAC(1)R) antagonist, PACAP(6-38), at 10(-6)M, but not with the PACAP/VIP receptor antagonist, VIP(6-28). PACAP-induced SL release was also attenuated by treatment with the calmodulin inhibitor, calmidazolium at 10(-6)M. This led us to explore the signal transduction mechanism up to SL release, and we examined whether PACAP-induced SL release is mediated by the adenylate cyclase (AC)/cAMP/protein kinase A (PKA)- or the phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP(3))/protein kinase C (PKC)-signaling pathway. PACAP-induced SL release was attenuated by treatment with the AC inhibitor, MDL-12330A, at 10(-5)M or with the PKA inhibitor, H-89, at 10(-5)M. PACAP-induced SL release was suppressed by treatment with the PLC inhibitor, U-73122, at 3 x 10(-6)M or with the PKC inhibitor, GF109203X, at 10(-6)M. These results suggest that PACAP can potentially function as a hypophysiotropic factor mediating SL release via the PAC(1)R and subsequently through perhaps the AC/cAMP/PKA- and the PLC/IP(3)/PKC-signaling pathways in goldfish pituitary cells.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces somatolactin release from cultured goldfish pituitary cells. 1954 Apr 24


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