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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian circadian clock genes Per1 and Per2 are rhythmically expressed not only in the suprachiasmatic nucleus where the mammalian circadian clock exists, but also in other brain regions and peripheral tissues. The induced circadian oscillation of Per genes after treatment with high concentrations of serum or various drugs in cultured cells suggests the ubiquitous existence of the oscillatory mechanism. These treatments also result in a rapid surge of expression of Per1. It has been shown that multiple signaling pathways are involved in Per1 gene induction in culture cells. We used a dispersed primary cell culture made up of mouse cerebellar granule cells to examine the stimuli inducing the mPer genes and their signaling pathways in neuronal tissues expressing mPer genes. We demonstrated that mPer1, but not mPer2, mRNA expression was dependent on the depolarization state controlled by extracellular KCl concentration in the granule cell culture. Nifedipine treatment reduced mPer1 induction, suggesting that mPer1 mRNA expression depends on intracellular calcium concentration regulated through a voltage-dependent Ca2+ channel. Transient mPer1 mRNA induction was observed after elevating KCl concentration in the medium from 5 mM to 25 mM. This increased expression was suppressed by a calmodulin antagonist, or CaMKII/IV inhibitor, but not by MEK inhibitors. Addition of pituitary adenylate cyclase-activating polypeptide-38 to the medium also induced transient Per1 gene expression. This induction was mimicked by dibutyryl-cAMP and suppressed by a protein kinase A (PKA) inhibitor, but not by MEK inhibitors. These results suggest that Ca2+/calmodulin-dependent protein kinase II/IV- and PKA-dependent pathways are involved in high-KCl and PACAP-induced mPer1 induction, respectively, and neural tissues use multiple signaling pathways for mPer1 induction similar to culture cells.
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PMID:Calcium and pituitary adenylate cyclase-activating polypeptide induced expression of circadian clock gene mPer1 in the mouse cerebellar granule cell culture. 1148 52

The cDNA encoding the glycoprotein alpha (GPalpha) subunit of tilapia (Oreochromis mossambicus) was partially cloned using RACE-polymerase chain reaction (PCR) technique. The amplified cDNA was found to be 583 bases long, and to consist of a portion of the signal peptide, the full sequence encoding the mature peptide (94 amino acids) and the 3' untranslated region. Northern blot analysis revealed a single band of approximately 600 bp. Alignment of the deduced amino acids of the mature protein showed that the tilapia GPalpha subunit shares more than 80% identity with that of other perciform fish (i.e. striped bass, sea bream and yellowfin porgy) and less than 70% with that of more taxonomically remote fish and other vertebrates. Exposure of dispersed tilapia pituitary cells to salmon gonadotropin-releasing hormone (sGnRH) elevated GPalpha mRNA levels via both PKC and cAMP-protein kinase A (PKA) pathways. The transcript levels were also regulated by pituitary adenylate cyclase activating polypeptide (PACAP) and neuropeptide Y (NPY), both acting through PKC and PKA pathways. Moreover, a combined treatment of PACAP or NPY with GnRH seems to have an additive effect on the GPalpha subunit gene transcription. These results suggest that in tilapia the expression of GPalpha subunit is regulated by GnRH mainly via PKC and PKA pathways. Furthermore, PACAP and NPY can elevate the GnRH-stimulated GPalpha subunit transcription and can directly affect the subunit mRNA levels, via the same transduction pathways.
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PMID:Tilapia glycoprotein hormone alpha subunit: cDNA cloning and hypothalamic regulation. 1150 Feb 38

The role of cAMP/cAMP-dependent protein kinase (PKA) on the late phase of exocytosis has been studied by amperometry on Ba(2+)-stimulated single bovine chromaffin cells. Forskolin (FSK) increases the intracellular cAMP levels in a concentration-dependent manner. Forskolin (100 nM) does not increase the number of exocytotic events, although it significantly increases the net granule content of catecholamines (CA), which is accompanied by a slowing of the process of degranulation. These effects are reversible, occur within 15 to 60 s, and are not due to newly synthesized CA. Isoprenaline, pituitary adenylate cyclase-activating polypeptide-38 or dB-cAMP reproduce FSK effects as does cholera toxin. The inhibition of phosphodiesterases with 3-isobutyl-1-methylxanthine mimics and potentiates the effect of FSK and isoprenaline. Rolipram and okadaic acid also produce a drastic increase in net granule content of CA, whereas H-89 attenuates the FSK response. These data indicate that cyclic AMP/PKA might favor the granule aggregation before its fusion with cell membrane and slow the late step of the exocytotic process.
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PMID:cAmp modulates exocytotic kinetics and increases quantal size in chromaffin cells. 1150 82

The present study was designed to test whether GnRH regulates pituitary adenylate cyclase-activating polypeptide mRNA levels in a stage-dependent manner during follicle development in the rat ovary. The granulosa cells of preovulatory and immature follicles obtained from PMSG- and estrogen-treated rats, respectively, were cultured in serum-free conditions in the presence of various hormones. GnRH receptor mRNA expression was detected in both preovulatory and immature granulosa cells and was down-regulated by gonadotropins. Treatment of preovulatory granulosa cells with GnRH agonist stimulated pituitary adenylate cyclase-activating polypeptide mRNA levels in a dose-dependent manner. In situ hybridization analysis of cultured preovulatory follicles revealed that GnRH-induced pituitary adenylate cyclase- activating polypeptide signals were detected in granulosa cells, but not thecal cells. In immature granulosa cells, cotreatment with GnRH agonist suppressed FSH-stimulated pituitary adenylate cyclase-activating polypeptide mRNA levels in a dose-dependent manner, whereas treatment with GnRH alone had no effect. Furthermore, treatment with GnRH antagonist inhibited LH-induced pituitary adenylate cyclase-activating polypeptide gene expression in preovulatory granulosa cells, whereas it stimulated FSH-induced pituitary adenylate cyclase-activating polypeptide gene expression in immature granulosa cells. Interestingly, GnRH-stimulated pituitary adenylate cyclase-activating polypeptide mRNA levels in preovulatory granulosa cells was inhibited by arachidonyltri fluoromethyl ketone, an inhibitor of phospholipase A(2), but not by an inhibitor of protein kinase A or C. Lastly, treatment of preovulatory follicles with pituitary adenylate cyclase-activating polypeptide antagonist suppressed GnRH-stimulated progesterone production during 6--9 h of culture. Taken together, these results demonstrate the stage-dependent regulation of pituitary adenylate cyclase-activating polypeptide mRNA levels by GnRH, the stimulatory and inhibitory effect in granulosa cells of preovulatory and immature follicles, respectively.
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PMID:Stage-dependent regulation of ovarian pituitary adenylate cyclase-activating polypeptide mRNA levels by GnRH in cultured rat granulosa cells. 1151 59

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a naturally occurring peptide found in the central nervous system that plays a role in somatosensory processing and activation of protein kinase A (PKA) and protein kinase C (PKC). Because activation of PKA or PKC results in reactivation of HSV-1 from latently infected embryonic neuronal cells, PACAP was used to evaluate HSV-1 activation from quiescently infected (QIF)-PC12 cells. Our studies demonstrate that physiologically relevant concentrations of PACAP38 and PACAP27 induce HSV-1 activation from QIF-PC12 cell cultures in a dose-dependent fashion. PACAP-induced activation of virus was significantly impaired by the PKA-inhibitor, H-89 (20 microM), whereas treatment with the PKC-inhibitor, GF109203X (1 microM), was without affect. Additionally, direct activation of PKA with cAMP analogs, 8-(4-chlorophenylthio)- and dibutyryl-cAMP, only partially mimicked the effect of PACAP on virus activation. Taken together, PACAP induced HSV-1 activation from QIF-PC12 cells involves the PKA and possibly cAMP-independent pathways. This report is the first to demonstrate that PACAP induces HSV-1 activation from a quiescent state and that this in vitro cell model is useful for studying early inductive events that lead to virus production from quiescence.
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PMID:Herpesvirus quiescence in neuronal cells IV: virus activation induced by pituitary adenylate cyclase-activating polypeptide (PACAP) involves the protein kinase A pathway. 1151 89

The hypothalamo-pituitary-adrenal (HPA) axis maintains a homeostatic response to stress, infection, or neoplasia. Inflammatory cytokines, including leukemia inhibitory factor (LIF), stimulate the HPA axis either directly at the pituitary corticotroph, or indirectly through induction of CRH or sympathetic noradrenergic neurons, and mediate the immuno-neuroendocrine interface. Unrestrained HPA axis activation leads, however, to immunosuppression. Because suppressor of cytokine signaling-3 (SOCS-3) is a potent inhibitor of LIF-activated HPA axis, and dynamic interactions between hypothalamus-derived cAMP-inducing neuropeptides and proinflammatory cytokines occur at the corticotroph level, we investigated SOCS-3 expression in response to peptides that stimulate cAMP including CRH, pituitary adenylate cyclase-activating polypeptide, and epinephrine. (Bu)2cAMP mediates induction of SOCS-3 promoter activity (6.7-fold +/- 0.5, P < 0.001) and SOCS-3 gene expression (4-fold +/- 0.8, P < 0.005) in a PKA-dependent manner. LIF and cAMP-inducing agents are additive on SOCS-3 promoter activity (22-fold +/- 2.6, LIF + (Bu)2cAMP vs. 7.3-fold +/- 0.6, LIF alone, P < 0.05) and on SOCS-3 transcription (11.3-fold +/- 2.1, LIF + (Bu)2cAMP vs. 9.3-fold +/- 1, LIF alone, P < 0.05), suggesting alternate pathways for LIF and cAMP-mediated corticotroph signaling. Similarly, LIF and CRH or pituitary adenylate cyclase-activating polypeptide are additive for SOCS-3 promoter activity and transcription (P < 0.05). Whereas signal transducer and activator of transcription 3 binding to the SOCS-3 promoter mediates LIF action, several SOCS-3 promoter regions containing cAMP-responsive elements are required for cAMP-PKA effect. Thus, both classes of POMC-inducing agents, cytokines as well as cAMP-inducing central peptides, regulate SOCS-3, providing a further level of negative HPA axis control during inflammation. These results indicate a sensitive intracellular autoregulation of corticotroph function.
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PMID:cAMP neuropeptide agonists induce pituitary suppressor of cytokine signaling-3: novel negative feedback mechanism for corticotroph cytokine action. 1168 19

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a basic 38-amino acid peptide, which acts through three main G protein-coupled VIP/PACAP receptor subtypes, called PAC1, VPAC1 and VPAC2. We have investigated the expression and function of PACAP and its receptors in the rat adrenal gland. Reverse transcription (RT)-polymerase chain reaction (PCR) and radioimmune assay (RIA) allowed the detection of PACAP expression as mRNA and protein exclusively in adrenal medulla (AM). RT-PCR and quantitative autoradiography, using [(125)I]PACAP and selective VIP/PACAP receptor ligands, demonstrated the expression of PAC1 only in AM, and VPAC1 and VPAC2 in both AM and zona glomerulosa (ZG), PACAP receptor expression being absent in zona fasciculata/reticularis (ZF/R). PACAP38 concentration-dependently increased aldosterone secretion from dispersed ZG cells and catecholamine secretion from AM tissue, the maximal effective concentration being 10(-7) M. ZF/R cells did not display any secretory response to PACAP38. Aldosterone response of ZG cells to 10(-7) M PACAP38 was unaffected by the PAC1-antagonist (A) PACAP(6-38), and significantly decreased by the VPAC1-A [Ac-His(1),D-Phe(2),Lys(15),Arg(16)]VIP(3-7) GRF(8-27)-NH(2). Catecholamine response of AM tissue to PACAP38 was reduced, but not abolished, by both PAC1-A and VPAC1-A. The VPAC2 agonist (ago) Ro25-1553 elicited sizeable secretory responses from both ZG cells and AM tissue. PACAP38 (10(-7) M) evoked a marked rise in cyclic-AMP (cAMP) and inositol-1,4,5-triphosphate (IP3) production by ZG cells and AM tissue. cAMP response of ZG cells was lowered by VPAC1-A, and that of AM tissue by both PAC1-A and VPAC1-A. IP3 response of ZG cells and AM tissue was unaffected by PAC1-A and decreased by VPAC1-A. VPAC2-ago did not affect cAMP release, but raised IP3 production by both ZG cells and AM tissue. Aldosterone response of ZG cells and catecholamine response of AM tissue to PACAP38 (10(-7) M) were reduced by the adenylate cyclase (AC) and phospholipase-C (PLC) inhibitors (I) SQ-22536 and U-73122, as well as by the protein kinase (PK)A-I H-89 and PKC-I calphostin-C. Conversely, the secretory responses of both ZG and AM preparations to VPAC2-ago were annulled by PLC-I, lowered by PKC-I, and unaffected by either AC-I or PKA-I. Collectively, our findings allow us to conclude that in the rat adrenals: i) PACAP biosynthesis exclusively occurs in the AM; ii) ZG cells are provided with functional VPAC1 and VPAC2 receptors, whose activation by PACAP evokes a moderate aldosterone response; iii) AM cells possess all the subtypes of VIP/PACAP receptors, whose activation by PACAP elicits a marked catecholamine response; and iv) PAC1 receptors are coupled to the AC-dependent cascade, VPAC1 receptors to both the AC- and PLC-dependent cascades, and VPAC2 receptors exclusively to the PLC-dependent cascade.
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PMID:Pituitary adenylate cyclase-activating polypeptide and PACAP receptor expression and function in the rat adrenal gland. 1183 29

Multiple neuroactive substances are secreted by neurons and/or glial cells and modulate the sensitivity to cell death. In the developing retina, it has been shown that increased intracellular levels of cAMP protect cells from degeneration. We tested the hypothesis that the neuroactive peptide pituitary adenylyl cyclase-activating polypeptide (PACAP) has neuroprotective effects upon the developing rat retina. PACAP38 prevented anisomycin-induced cell death in the neuroblastic layer (NBL) of retinal explants, and complete inhibition of induced cell death was obtained with 1 nm. A similar protective effect was observed with PACAP27 and with the specific PAC1 receptor agonist maxadilan but not with glucagon. Photoreceptor cell death induced by thapsigargin was also prevented by PACAP38. The neuroprotective effect of PACAP38 upon the NBL could be reverted by the competitive PACAP receptor antagonist PACAP6-38 and by the specific PAC1 receptor antagonist Maxd.4. Molecular and immunohistochemical analysis demonstrated PAC1 receptors, and treatment with PACAP38 induced phospho-cAMP-response element-binding protein immunoreactivity in the anisomycin-sensitive undifferentiated postmitotic cells within the NBL. PACAP38 produced an increase in cAMP but not inositol triphosphate, and treatment with the cAMP-dependent protein kinase inhibitor R(p)-cAMPS blocked the protective effect of PACAP38. The results indicate that activation of PAC1 receptors by PACAP38 modulates cell death in the developing retina through the intracellular cAMP/cAMP-dependent protein kinase pathway.
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PMID:Pituitary adenylyl cyclase-activating polypeptide prevents induced cell death in retinal tissue through activation of cyclic AMP-dependent protein kinase. 1184 14

Generation of distinct cell types and numbers in developing cerebral cortex is subject to regulation by extracellular factors that positively or negatively control precursor proliferation. Although signals stimulating proliferation are well described, factors halting cell cycle progression are less well defined. At the molecular level, production and association of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) regulate cycle progression. We now report that the endogenous peptide, pituitary adenylate cyclase activating polypeptide (PACAP), negatively regulates the cell cycle by inhibiting p57Kip2-dependent CDK2 activity in embryonic cortex. Protein levels of CDK2 and members of the CIP/KIP family of CKIs (p27Kip1, p57Kip2) were detected in developing rat cortex from embryonic day 13.5 through postnatal day 2. With advancing development, CDK2 protein levels decreased, whereas CKI expression increased, suggesting that stimulatory and inhibitory cycle proteins control cell cycle exit. Using a well defined, nonsynchronized, 8 hr precursor culture, PACAP decreased the fraction of cells crossing the G1/S boundary, inhibiting DNA synthesis by 35%. CDK2 kinase activity was inhibited 75% by PACAP, whereas kinase protein and its regulatory cyclin E subunit were unaffected. Moreover, decreased kinase activity was accompanied by a twofold increase in levels of p57Kip2 protein, but not p21Cip1 or p27Kip1, suggesting that p57Kip2 mediates PACAP anti-mitogenic effects. Indeed, immunoprecipitation of CDK2 complex revealed increased p57Kip2 association with the kinase and concomitant reduction in free inhibitor after PACAP exposure, suggesting that p57Kip2 interactions directly regulate CDK2 activity. These observations establish a mechanism whereby anti-mitogenic signals actively induce cell cycle withdrawal in developing cortex.
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PMID:Pituitary adenylate cyclase activating polypeptide anti-mitogenic signaling in cerebral cortical progenitors is regulated by p57Kip2-dependent CDK2 activity. 1188 Apr 88

There is ample information on the hypophysiotropic function of pituitary adenylate cyclase-activating polypeptide (PACAP) and neuropeptide Y (NPY) in fish as in mammals, although evidence as to their direct effects on gonadotropic cells is scarce. We have previously reported that NPY and PACAP38 augment gonadotropin-releasing hormone (GnRH)-induced expression of glycoprotein alpha (alpha) subunit gene in the teleost fish, tilapia. The aim of the present study was to elucidate possible direct effects of these peptides on gonadotropin subunit gene expression in culture of tilapia pituitary cells, as well as the transduction pathways involved. Both NPY and PACAP38 (0.001-10 nM) increased the level of phosphorylated extracellular signal-regulated kinase (pERK) dose-dependently, reaching a peak at 0.1 and 0.01 nM, respectively. Inhibition of protein kinase C (PKC) by GF109203X (GF; 0.01-10 nM) suppressed NPY-stimulated pERK levels and its effect on alpha and luteinizing hormone (LH) beta subunit mRNA levels. However, NPY had no effect on follicle stimulating hormone (FSH) beta mRNA levels. NPY-elevated alpha, LHbeta mRNA and pERK levels were also attenuated by inhibition of protein kinase A (PKA) with H89 (0.01-10 nM). Exposure of the cells to the MAPK kinase (MEK) inhibitor (PD98059; PD 10, 25 and 50 microM) completely blocked NPY-induced ERK activity. In addition, this inhibitor abated the alpha and LHbeta mRNA responses to NPY. Similar experiments conducted to elucidate PACAP38 signaling revealed that PACAP38 (0.01 nM) elevated all three-gonadotropin subunit gene expression via both PKC-ERK and PKA-ERK cascades. It is suggested that both NPY and PACAP38 act directly on gonadotropes to elevate gonadotropin subunit gene expression. Whereas the expression of alpha and LHbeta subunit genes is regulated by both NPY and PACAP, the effect on the FSHbeta transcript is elicited only by PACAP38. NPY and PACAP38 stimulatory actions are mediated via protein kinase C (PKC) and protein kinase A (PKA), converging at the MEK-ERK cascade. These findings represent one of the fine tuning levels that differentially regulates gonadotropin subunit gene expression.
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PMID:Pituitary adenylate cyclase activating polypeptide and neuropeptide Y regulation of gonadotropin subunit gene expression in tilapia: role of PKC, PKA and ERK. 1191 88


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