Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Characteristics of pituitary adenylate cyclase-activating polypeptide (PACAP)-induced increase of Ca(2+) entry and catecholamine (CA) release were studied in bovine adrenal medullary chromaffin cells. PACAP induced intracellular free Ca(2+) concentration ([Ca(2+)](i)), showing an initial transient [Ca(2+)](i) rise followed by a sustained rise and CA release, which were not blocked by the blocking agents for nicotinic acetylcholine receptor (nAChR) channel, the voltage-dependent Ca(2+) channel (VOC), or the Na(+) channel. The sarcoendoplasmic Ca(2+)-ATPase inhibitors thapsigargin and cyclopiazonic acid did not affect the PACAP-induced sustained rise of [Ca(2+)](i), but did inhibit the initial [Ca(2+)](i) rise. In cells pretreated with cyclopiazonic acid or membrane-permeable, low-affinity Ca(2+) chelator N',N',N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, PACAP further stimulated the entry of Ca(2+) or Mn(2+), whereas these treatments masked [Ca(2+)](i) dynamics induced by bradykinin. PACAP-induced sustained [Ca(2+)](i) rise and Mn(2+) entry were enhanced by acidic extracellular solution and reduced by alkalinization, whereas thapsigargin-induced Mn(2+) entry was regulated by the opposite. PACAP-induced [Ca(2+)](i) rise and Mn(2+) entry were not affected by blockers of cAMP-dependent protein kinase, phospholipase C, or protein kinase C. All store-operated Ca(2+) channel (SOC) blocking agents tested inhibited thapsigargin-induced Mn(2+) entry. 1(beta-[3-(4-Methoxyphenyl)-propoxy]-4-methoxyphenylethyl)-1H-imidazole hydrochloride (SK&F 96365), (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide, and econazole inhibited PACAP-induced Ca(2+) or Mn(2+) entry, whereas GdCl(3), 7,8-benzoflavone, nor-dihydroguaiaretic acid, 5-nitro-2-(3-phenylpropylamino)benzoic acid, fulfenamic acid, and niflumic acid did not. SK&F 96365 and econazole but not GdCl(3) inhibited PACAP-induced CA release. These results suggest that PACAP activates a novel Ca(2+) entry pathway associated with sustained CA release independent of the nAChR channel, VOC and SOC, activated by acid pH, with different sensitivity to blockers of SOC. This pathway may provide a useful model for the study of receptor-operated Ca(2+) entry.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces a sustained increase in intracellular free Ca(2+) concentration and catechol amine release by activating Ca(2+) influx via receptor-stimulated Ca(2+) entry, independent of store-operated Ca(2+) channels, and voltage-dependent Ca(2+) channels in bovine adrenal medullary chromaffin cells. 1218 54

The endogenous pacemaker activity of the suprachiasmatic nuclei (SCN; the master clock in mammals) is regulated by photic information relayed from the retina to the SCN via the retinohypothalamic tract (RHT). Recent work has revealed that glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) are stored in RHT nerve terminals and function in a coordinated manner to regulate clock timing. To address this interaction on a cellular level, Fura-2 Ca(2+) digital imaging was employed and the effects of PACAP on glutamate evoked Ca(2+) transients in SCN neurons were examined. Pretreatment of SCN neurons with PACAP markedly potentiated Ca(2+) transients elicited by both exogenous glutamate application and synaptically released glutamate. Many neurons became responsive to glutamate only after PACAP administration, suggesting that PACAP sets the lower concentration threshold required for glutamate to initiate a robust rise in postsynaptic cytosolic Ca(2+). Facilitation of glutamate-induced Ca(2+) transients was inhibited by nimodipine, indicating that PACAP potentiates L-type Ca(2+) channel activity. The modulatory actions of PACAP were inhibited by antagonizing signaling via the p42/44 mitogen-activated protein kinase (MAPK) signal transduction cascade. Immunocytochemistry and Western analysis confirmed that PACAP stimulates MAPK activity at doses and time points shown to potentiate Ca(2+) influx. Down-regulation of protein kinase C (PKC) with the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) or PKC inhibition with bisindolylmaleimide attenuated the actions of PACAP, indicating that PKC also couples PACAP to potentiation of depolarization-induced Ca(2+) transients. The data presented here identify potentially important mechanisms by which PACAP regulates SCN physiology.
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PMID:PACAP potentiates L-type calcium channel conductance in suprachiasmatic nucleus neurons by activating the MAPK pathway. 1220 58

Although positive and negative signals control neurogenesis in the embryo, factors regulating postnatal proliferation are less well characterized. In the vertebrate cerebellum, Sonic Hedgehog (Shh) is an efficacious mitogen for cerebellar granule neuron precursors (GNPs), and mutations activating the Shh pathway are linked to medulloblastoma, a tumor derived from GNPs. Although the mitogenic effects of Shh can be blocked by increasing cAMP or protein kinase A activity, the physiological factors antagonizing this stimulation are undefined. In the embryo, pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 1 (PAC1) signaling regulates neural precursor proliferation. We now show that in the developing cerebellum, PAC1 mRNA colocalizes with gene transcripts for Shh receptor Patched 1 and target gene Gli1 in the external germinal layer. We consequently investigated the interactions of PACAP and Shh in proliferation of purified GNPs in culture. Shh exhibited mitogenic activity in both rat and mouse cultures, stimulating DNA synthesis approximately 10-fold after 48 hr of exposure. PACAP markedly inhibited Shh-induced thymidine incorporation by 50 and 85% in rat and mouse GNPs, respectively, but did not significantly affect the stimulation induced by other mitogens. This selective effect was reproduced by the specific PAC1 agonist maxadilan, as well as by the adenylate cyclase activator forskolin, suggesting that PAC1 provides a potent inhibitory signal for Shh-induced proliferation in developing cerebellum. In contrast, in the absence of Shh, PACAP and maxadilan modestly stimulated DNA synthesis, an effect reproduced by activating protein kinase C. These observations suggest that G-protein-coupled receptors, such as PAC1, serve as sensors of environmental cues, coordinating diverse neurogenetic signals.
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PMID:Pituitary adenylate cyclase-activating polypeptide and sonic hedgehog interact to control cerebellar granule precursor cell proliferation. 1241 50

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an adrenomedullary cotransmitter that along with acetylcholine is responsible for driving catecholamine and neuropeptide biosynthesis and secretion from chromaffin cells in response to stimulation of the splanchnic nerve. Two neuropeptides whose biosynthesis is regulated by PACAP include enkephalin and vasoactive intestinal polypeptide (VIP). Occupancy of PAC1 PACAP receptors on chromaffin cells can result in elevation of cyclic AMP, inositol phosphates, and intracellular calcium. The proenkephalin A and VIP genes are transcriptionally responsive to signals generated within all three pathways, and potentially by combinatorial activation of these pathways as well. The characteristics of PACAP regulation of enkephalin and VIP biosynthesis were examined pharmacologically for evidence of involvement of several serine/threonine protein kinases activated by cAMP, IP3, and/or calcium, including calmodulin kinase II, protein kinase A, and protein kinase C. Evidence is presented for the differential involvement of these protein kinases in regulation of enkephalin and VIP biosynthesis in chromaffin cells, and for a prominent role of the mixed-function (tyrosine and serine/threonine) MAP kinase family in mediating transcriptional activation of neuropeptide genes by PACAP.
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PMID:Role of protein kinases in neuropeptide gene regulation by PACAP in chromaffin cells: a pharmacological and bioinformatic analysis. 1243 68

The small GTPases Ras or Rap1 were suggested to mediate the stimulatory effect of some G protein-coupled receptors on ERK activity in neuronal cells. Accordingly, we reported here that pituitary adenylate cyclase-activating polypeptide (PACAP), whose G protein-coupled receptor triggers neuronal differentiation of the PC12 cell line via ERK1/2 activation, transiently activated Ras and induced the sustained GTP loading of Rap1. Ras mediated peak stimulation of ERK by PACAP, whereas Rap1 was necessary for the sustained activation phase. However, PACAP-induced GTP-loading of Rap1 was not sufficient to account for ERK activation by PACAP because 1) PACAP-elicited Rap1 GTP-loading depended only on phospholipase C, whereas maximal stimulation of ERK by PACAP also required the activity of protein kinase A (PKA), protein kinase C (PKC), and calcium-dependent signaling; and 2) constitutively active mutants of Rap1, Rap1A-V12, and Rap1B-V12 only minimally stimulated the ERK pathway compared with Ras-V12. The effect of Rap1A-V12 was dramatically potentiated by the concurrent activation of PKC, the cAMP pathway, and Ras, and this potentiation was blocked by dominant-negative mutants of Ras and Raf. Thus, this set of data indicated that GPCR-elicited GTP loading of Rap1 was not sufficient to stimulate efficiently ERK in PC12 cells and required the permissive co-stimulation of PKA, PKC, or Ras.
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PMID:Stimulation of the ERK pathway by GTP-loaded Rap1 requires the concomitant activation of Ras, protein kinase C, and protein kinase A in neuronal cells. 1247 65

Astroglial cells synthesize and release endozepines, neuropeptides that are related to the octadecaneuropeptide ODN. Glial cells also express PACAP/VIP receptors. We have investigated the possible effect of PACAP on the release of ODN-like immunoreactivity (ODN-LI) by cultured rat astrocytes. Administration of PACAP27 and PACAP38 induced a concentration-dependent increase in secretion of ODN-LI whereas VIP was approximately 1000-fold less potent. The maximum effect of PACAP38 occurred after 5 min, then gradually declined during the next 10 min. The stimulatory effects of PACAP and VIP were abrogated by the PACAP antagonist PACAP6-38. PACAP38 stimulated cAMP formation, activated polyphosphoinositide turnover, and provoked calcium mobilization from IP3-sensitive pools. The PKA inhibitor H89 suppressed PACAP-induced secretion of ODN-LI, whereas PLC inhibitor U73122 and the PKC inhibitor chelerythrine had no effect. In contrast, U73122 restored the stimulatory action of PACAP on ODN-LI release and cAMP formation during prolonged (15 min) incubation with the peptide, and this effect was prevented by PMA. The present results demonstrate that PACAP stimulates endozepine release through activation of PAC1 receptors coupled to the AC/PKA pathway. Our data also show that activation of the PLC/PKC pathway down-regulates the effect of PACAP on endozepine release.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates endozepine release from cultured rat astrocytes via a PKA-dependent mechanism. 1252 8

The sphingolipid metabolites, ceramides, are critical mediators of the cellular stress response and play an important role in the control of programmed cell death. In particular, ceramides have been shown to induce apoptosis of cerebellar granule cells. We show that pituitary adenylate cyclase-activating polypeptide (PACAP) prevents C2-ceramide-induced apoptosis. The neuroprotective effect of PACAP was dose-dependent and blocked by its antagonist, PACAP6-38, whereas the PACAP-related peptide VIP was inactive. The effect of PACAP on cell survival was mimicked by dibutyryl-cAMP (dbcAMP) and forskolin and prevented by the MEK inhibitor U0126, indicating that both the adenylyl-cyclase and MAP-kinase pathways contribute to the neuroprotective action of the peptide. C2-ceramide and PACAP induced opposite effects on phosphorylated forms of ERK and JNK without affecting the total amounts of ERK and JNK, suggesting that a balance between these two MAP-kinases is critical for the cell survival/death decision. The effect of PACAP on ERK phosphorylation was blocked by U0126, but was not affected by H89 or chelerythrine indicating that PACAP activates ERK through a PKA- and PKC-independent mechanism. C2-ceramide induced a time-dependent activation of caspase-3, enhanced the amount of cleaved caspase-3 and stimulated the DNA fragmentation process, while PACAP strongly inhibited the C2-ceramide-induced activation of caspase-3, reduced the expression of cleaved caspase-3 and blocked DNA fragmentation. Taken together, the present results show that C2-ceramide induces apoptosis of cerebellar granule cells through a mechanism involving activation of caspase-3. Our data also demonstrate that PACAP is a potent inhibitor of C2-ceramide-induced apoptosis.
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PMID:Pituitary adenylate cyclase-activating polypeptide prevents C2-ceramide-induced apoptosis of cerebellar granule cells. 1269 97

Neurohormones similar to those of mammals are carried in fish by hypothalamic nerve fibers to regulate directly follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Gonadotropin-releasing hormone (GnRH) stimulates the secretion of FSH and LH and the expression of the glycoprotein hormone alpha (GPalpha), FSHbeta, and LHbeta, as well as their secretion. Its signal transduction leading to LH release is similar to that in mammals although the involvement of cyclic AMP-protein kinase A (cAMP-PKA) cannot be ruled out. Dopamine (DA) acting through DA D2 type receptors may inhibit LH release, but not that of FSH, at sites distal to activation of protein kinase C (PKC) and PKA. GnRH increases the steady-state levels of GPalpha, LHbeta, and FSHbeta mRNAs. Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and neuropeptide Y (NPY) potentiate GnRH effect on gonadotropic cells, and also act directly on the pituitary cells. Whereas PACAP increases all three subunit mRNAs, NPY has no effect on that of FSHbeta. The effect of these peptides on the expression of the gonadotropin subunit genes is transduced differentially; GnRH regulates GPalpha and LHbeta via PKC-ERK and PKA-ERK cascades, while affecting the FSHbeta transcript through a PKA-dependent but ERK-independent cascade. The signals of both NPY and PACAP are transduced via PKC and PKA, each converging at the ERK level. NPY regulates only GPalpha- and LHbeta-subunit genes whereas PACAP regulates the FSHbeta subunit as well. Like those of the mammalian counterparts, the coho salmon LHbeta gene promoter is driven by a strong proximal tripartite element to which three different transcription factors bind. These include Sf-1 and Pitx-1 as in mammals, but the function of the Egr-1 appears to have been replaced by the estrogen receptor (ER). The GnRH responsive region in tilapia FSHbeta 5' flanking region spans the canonical AP1 and CRE motifs implicating both elements in conferring GnRH responsiveness. Generally, high levels of gonadal steroids are associated with high LHbeta transcript levels whereas those of FSHbeta are reduced when pituitary cells are exposed to high steroid levels. Gonadal or hypophyseal activin also participate in the regulation of FSHbeta and LHbeta mRNA levels. However, gonadal effects are dependent on the gender and stage of maturity of the fish.
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PMID:Regulation of fish gonadotropins. 1269 92

Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a potent activator of cyclic AMP formation in the chick brain. The peptide also stimulates inositol phosphates accumulation and protein kinase C (PKC) activity in the chick cerebral cortex. In this work, we analyzed whether PACAP38-induced increase in cyclic AMP production in the chick cerebrum can be modified by a PKC pathway. 4Beta-phorbol 12,13-dibutyrate (4beta-PDB), a PKC activator, did not significantly affect the PACAP38-evoked increase in [3H]cyclic AMP production in [3H]adenine-prelabeled slices of the chick cerebral cortex. Of the tested PKC inhibitors, i.e. chelerythrine, H-7, NPC-15437 and staurosporine, only chelerythrine markedly decreased, in a concentration-dependent manner, the PACAP38-activated cyclic AMP accumulation in the chick cerebrum. These results suggest that (1) the process of cyclic AMP production stimulated by PACAP in the cerebral cortex of chick is not PKC-dependent, and that (2) chelerythrine, a widely used PKC inhibitor, influences the intracellular signaling pathway(s) associated with PACAP receptors in the chick brain in a way not involving PKC.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP)-evoked increase in cyclic AMP production in chick cerebral cortex: lack of a role of the protein kinase C pathway. 1292 54

Novel neurotrophin-1/B cell stimulating factor-3 (NNT-1/BSF-3) is a gp130 cytokine potently stimulating corticotroph proopiomelanocortin gene expression and ACTH secretion by a Janus kinase-signal transducer and activator of transcription (JAK-STAT)-dependent mechanism. In the current study, we examined the regulation of NNT-1/BSF-3 mRNA expression in murine pituitary folliculostellate TtT/GF cells using Northern blot technique. A 5- to 9-fold and a 4- to 7-fold induction in NNT-1/BSF-3 mRNA expression was observed between 2 and 6 h stimulation with the protein kinase C (PKC) stimulus phorbol-12-myristate-13-acetate (100 nm) and the protein kinase A (PKA) stimulus Bu(2)cAMP (5 mm), respectively. Pituitary adenylate cyclase-activating polypeptide (PACAP-38, 50 nm) and vasoactive intestinal peptide (VIP, 50 nm) also stimulated NNT-1/BSF-3 mRNA expression 5- to 9-fold between 2 and 6 h. Preincubation with PKC and PKA inhibitors such as H-7 (20 microm), GF109203X (50 microm), and H-89 (50 microm) decreased the stimulatory effects of PACAP and VIP. Both PACAP-38 and VIP also rapidly induced ERK1/2 phosphorylation and their stimulatory effect on NNT-1/BSF-3 mRNA expression was reduced by the MAPK kinase/ERK kinase (MEK) inhibitor U0126 (10 microm). Dexamethasone (10(-7) m) was a potent inhibitor of phorbol-12-myristate-13-acetate-induced NNT-1/BSF-3 expression. RT-PCR analysis demonstrated TtT/GF cells to express the short and the hop variant but not the hip variant of the PACAP-1 receptor (PAC1-R). In addition, TtT/GF cells express the VIP/PACAP-2 receptor (VPAC2-R). In summary, NNT-1/BSF-3 is expressed in pituitary folliculostellate TtT/GF cells and induced by PKC-, PKA-, and ERK1/2-dependent mechanisms. The novel gp130 cytokine NNT-1/BSF-3 derived from folliculostellate cells might act as a paracrine neuroimmunoendocrine modulator of pituitary corticotroph function.
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PMID:Expression of novel neurotrophin-1/B-cell stimulating factor-3 (NNT-1/BSF-3) in murine pituitary folliculostellate TtT/GF cells: pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide-induced stimulation of NNT-1/BSF-3 is mediated by protein kinase A, protein kinase C, and extracellular-signal-regulated kinase1/2 pathways. 1460 1


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