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)

A region of the brain believed to be important in the CNS response to stress is the locus coeruleus, the predominant site of noradrenergic cell bodies. Corticotrophin releasing hormone (CRH) is the primary hypothalamic releasing hormone responsible for the activation of the pituitary-adrenal axis in response to stress and, in this study, we employed a locus coeruleus-like cell line, CATH.a, to investigate the modulation of receptor signalling pathways by CRH. Pituitary adenylyl cyclase-activating polypeptide (PACAP) (10 nM), vasoactive intestinal peptide (VIP) (1 microM) and carbachol (1 mM) produced transient increases in intracellular [Ca2+]. The inhibition of the carbachol (1 mM) response by CRH was concentration-dependent (EC50 = 154 +/- 1.8 nM). Calcium responses to sub-maximally effective concentrations of PACAP (5 nM), VIP (400 nM) and carbachol (1 mM) were abolished by prior exposure to CRH (1 microM). At the concentrations employed, CRH and VIP both substantially increased intracellular [3H]-cyclic AMP accumulation. The adenylyl cyclase activator forskolin (10 microM) was also effective at eliminating the agonist-induced calcium responses. Incubation with the cell permeant cyclic AMP analogue dibutyryl cyclic AMP (dbcAMP) (1 mM), an activator of protein kinase A (PKA), for 12 min prior to agonist exposure similarly abolished the intracellular calcium response to carbachol. Carbachol increased [3H]-inositol phosphate ([3H]-IP) accumulation to a maximum of 2.4 +/- 0.11-fold basal (EC50 = 6.75 +/- 0.26 microM). PACAP produced a much greater accumulation (19.9 +/- 2.1 fold basal; EC50 = 24 nM). In the presence of forskolin (10 microM), neither carbachol- nor PACAP-induced [3H]-IP accumulation was significantly different from in its absence. These results demonstrate that CRH inhibits receptor-mediated intracellular calcium responses in a locus coeruleus-like cell line possibly via activation of PKA. This modulation could be important in controlling neuronal function in vivo in stressful situations in which the levels of CRH are increased in the locus coeruleus.
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PMID:Inhibition of receptor-mediated calcium responses by corticotrophin-releasing hormone in the CATH.a cell line. 1019 97

Pituitary adenylate cyclase-activating peptide (PACAP) is transiently expressed in ovarian granulosa/lutein cells from eCG/hCG-treated rats, and in vitro immunoneutralization of endogenously released PACAP inhibits acute progesterone secretion and subsequent luteinization in such cells. This suggests that PACAP mediates locally some of the effects of the LH surge, but the putative PACAP receptor(s) involved in such an auto or paracrine activity is presently unknown. Reverse-transcription polymerase chain reaction with specific primers to the three cloned PACAP-binding receptors called PAC(1), VPAC(1), and VPAC(2) demonstrated both PAC(1) and VPAC(2) mRNA in extracts from preovulatory follicular cells. Radioligand-binding assays revealed the presence of high-affinity binding sites with characteristics of these two receptors on the intact cells, and autoradiography demonstrated that the binding was restricted to a minor proportion of the follicular cells as well as the oocytes. Pituitary adenylate cyclase-activating peptide and vasoactive intestinal peptide (VIP) dose-dependently stimulated cAMP accumulation and acute progesterone accumulation. Forskolin and db-cAMP also stimulated acute progesterone accumulation, and the protein kinase A inhibitor H89 dose-dependently inhibited peptide induced acute progesterone accumulation, suggesting involvement of cAMP and the protein kinase A pathway in the process. In conclusion, two of the three PACAP binding receptors are present on preovulatory follicular cells and are involved in the effects of PACAP on acute progesterone production. The data provide further evidence to establish PACAP as an auto- or paracrine regulator of LH-induced acute progesterone production in rat preovulatory follicles.
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PMID:Pituitary adenylate cyclase-activating peptide stimulates acute progesterone production in rat granulosa/Lutein cells via two receptor subtypes. 1085 61

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel member of the secretin-glucagon peptide family. In mammals, this peptide has been located in a wide range of tissues and is involved in a variety of biological functions. In lower vertebrates, especially fish, increasing evidence suggests that PACAP may function as a hypophysiotropic factor regulating pituitary hormone secretion. PACAP has been identified in the brain-pituitary axis of representative fish species. The molecular structure of fish PACAP is highly homologous to mammalian PACAP. The prepro-PACAP in fish, however, is distinct from that of mammals as it also contains the sequence of fish GHRH. In teleosts, the anterior pituitary is under direct innervation of the hypothalamus and PACAP nerve fibers have been identified in the pars distalis. Using the goldfish as a fish model, mRNA transcripts of PACAP receptors, namely the PAC1 and VPACI receptors, have been identified in the pituitary as well as in various brain areas. Consistent with the pituitary expression of PACAP receptors, PACAP analogs are effective in stimulating growth hormone (GH) and gonadotropin (GTH)-II secretion in the goldfish both in vivo and in vitro. The GH-releasing action of PACAP is mediated via pituitary PAC1 receptors coupled to the adenylate cyclase-cAMP-protein kinase A and phospholipase C-IP3-protein kinase C pathways. Subsequent stimulation of Ca2+ entry through voltage-sensitive Ca2+ channels followed by activation of Ca2+-calmodulin protein kinase II is likely the downstream mechanism mediating PACAP-stimulated GH release in goldfish. Although the PACAP receptor subtype(s) and the associated post-receptor signaling events responsible for PACAP-stimulated GTH-II release have not been characterized in goldfish, these findings support the hypothesis that PACAP is produced in the hypothalamus and delivered to the anterior pituitary to regulate GH and GTH-II release in fish.
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PMID:Pituitary adenylate cyclase activating polypeptide as a novel hypophysiotropic factor in fish. 1094 84

Cis-unsaturated free fatty acids (FFA) like oleic acid are strong blockers of both basal and stimulated GH secretion in vivo by acting directly on the somatotroph cell. Several lines of evidence suggest that this inhibitory action is the result of a perturbation of the function of several plasma membrane integral proteins. It has been reported recently that cis-FFA are able to block several steps in the inositolphosphates/phospholipase C/Ca2+ (InsPs/PLC/Ca2+) signal transduction pathway triggered by the activation of the TRH receptor. In this paper we present evidence showing that the inhibition of growth hormone (GH) and prolactin (PRL) secretion by cis-FFA in vitro is also exerted at several different levels on the cAMP-protein kinase A (cAMP/PKA) pathway triggered by the stimulation of the vasoactive intestinal peptide (VIP) receptor in pituitary clonal cells. By means of a sequential analysis of signal transduction events, we observed that cis-unsaturated FFA; (1) reduce the activity of adenylate cyclase; (2) perturb the activity of protein kinase A; (3) suppress the VIP-triggered Ca2+ influx, and (4) do not perturb VIP binding or the homologous desensitization of the VIP receptor.
Pituitary 1998 Apr
PMID:Cis-unsaturated free fatty acids block VIP-mediated GH and PRL secretion by perturbing the cAMP/protein kinase A pathway. 1108 Nov 80

The proopiomelanocortin (POMC) gene expressed in corticotrophs of the anterior pituitary encodes several biologically active peptides and is primarily under the positive control of hypophysiotropic factors (e.g. corticotropin releasing hormone). Using AtT20 cells as a model, we show that these factors increase levels of POMC primary RNA transcripts representative of a transcriptional activation of the gene. This effect is mimicked by several activators of the cAMP signaling pathway. Inhibition of protein synthesis with cycloheximide did not modify the CRH-induced increase in POMC hnRNA suggesting that these early effects are mediated by preexisting transcription factors. Using a reporter gene containing 706 bp of the POMC promoter region, we observe transcriptional activation with the same compounds, their effects being abolished when protein kinase A (PKA) is inactivated by a dominant inhibitory mutant. Promoter deletion analyses mapped an essential cAMP inducible element within the first exon of the POMC gene. This element (PTRE: TGACTAA) located at nucleotides +41/+47 was shown to bind the cAMP responsive element binding protein (CREB) by gel shift analyses and confers strong transcriptional activation by an expression vector coding a CREB-VP16 activator domain fusion protein. Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE. Taken together, these results show that the major hypophysiotropic factors stimulate POMC transcription through a signaling cascade that involves PKA and CREB.
Pituitary 1998 Apr
PMID:Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein. 1108 Nov 81

Pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor type 1 (PAC(1)) signaling and desensitization were investigated in human retinoblastoma Y-79 cells. Concentration-dependent stimulation of cAMP accumulation was observed in Y-79 cells incubated for 30 min with PACAP38, PACAP27, or VIP (10(-12) to 10(-6) M). The following EC(50) values were calculated: PACAP38, 24+/-3 pM; PACAP27, 99+/-8 pM; and VIP, 29+/-3 nM. Homologous desensitization of PAC(1) receptors in Y-79 cells pretreated with 10 nM PACAP38 or PACAP27 for 60 min was characterized by a 30-50% reduction in PACAP-stimulated cAMP accumulation (p<0.0001) and a two- to fivefold rightward shift in EC(50) values (p<0.0001). PAC(1) receptor desensitization was not accompanied by a reduction in PAC(1) mRNA expression. We concluded that the desensitizing effect of PACAP38 was homologous because neither corticotropin-releasing factor- nor (-)-isoproterenol-stimulated cAMP accumulation was altered by PACAP38 preincubation. Pretreating Y-79 cells with the protein kinase A (PKA) inhibitor H89 failed to inhibit homologous PAC(1) receptor desensitization. Similarly, pretreating Y-79 cells with the protein kinase C (PKC) inhibitors staurosporine or bisindolylmaleimide failed to alter homologous PAC(1) receptor desensitization. Although activation of PKA by dibutyryl cAMP or forskolin did not desensitize PAC(1) receptors, direct activation of PKC by PMA heterologously desensitized PAC(1) receptors, reducing cAMP accumulation 34.2+/-2.2% (p<0.001). Using RT-PCR, mRNA levels for G-protein-coupled receptor kinase 3 (GRK3), but not GRK2, were found to increase 2.2- to 4.8-fold in Y-79 cells exposed to PACAP38 for 10 min to 24 h (p<0.001). PAC(1) receptor desensitization decreased 72.5+/-4.3% (p<0.001) in Y-79 cells transfected with a GRK3 antisense cDNA construct that also reduced GRK3 protein expression 48.5+/-7.9% (p<0.0005). These experiments demonstrate that GRK3 plays an important role in the homologous desensitization of retinoblastoma PAC(1) receptors, whereas PKC, but not PKA, contributes to the heterologous desensitization of retinoblastoma PAC(1) receptors.
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PMID:G-protein-coupled receptor kinase 3- and protein kinase C-mediated desensitization of the PACAP receptor type 1 in human Y-79 retinoblastoma cells. 1116 32

Pituitary adenylate cyclase activating peptide (PACAP) may play a role in neurogenesis, nerve injury, and neural tumor growth. A PACAP ligand receptor system functionally coupled to cAMP production was found to be expressed in the embryonic mouse neural tube at the onset of neurogenesis. PACAP was found to inhibit DNA synthesis and antagonize sonic hedgehog signaling in cells isolated from the neural tube, suggesting that PACAP interacts with patterning factors to regulate neurogenesis and phenotypic specification in the developing CNS. PACAP and PACAP receptor (PAC1) mRNA levels were strongly increased and decreased, respectively, in motor neurons in adult rats after facial nerve axotomy, indicating that PACAP may also act in nerve regeneration. Experiments using a neuroblastoma tumor cell line model indicate that PACAP may execute growth-related functions by activating MAP kinase in addition to cAMP-dependent protein kinase A.
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PMID:PACAP action in nervous system development, regeneration, and neuroblastoma cell proliferation. 1119 16

Pituitary tumors constitute 10% of intracranial neoplasms and are mostly benign, monoclonal adenomas derived from single mutant cells. Pituitary oncogenes have been intensively studied and three of them, gsp, ccnd1, and PTTG are abundant in significant numbers of cases. gsp is present in approximately 40% of Caucasian patients with GH-secreting tumors and results from a mutated, constitutively active alpha subunit of Gs protein. Persistent activation of the cAMP-PKA-CREB pathway may lead to uncontrolled cell proliferation and GH secretion. ccnd1 is overexpressed cyclin D1, and cyclin D1 gene is amplified in some pituitary tumors. PTTG is expressed in most pituitary tumors. PTTG is localized to both the nucleus and cytoplasm and interacts with several protein partners. At least three tumorigenesis mechanisms are proposed for human PTTG. 1) PTTG and FGF form a positive feedback loop and stimulate tumor vascularity. 2) PTTG transactivates c-myc or other pro-proliferation genes. 3) PTTG overexpression causes aneuploidy. PTTG expression activates p53 and causes p53-dependent and -independent apoptosis. Due to lack of functional human pituitary cell cultures and appropriate animal models for pituitary tumors, many of the results reviewed here are obtained from heterologous systems.
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PMID:Oncogene activation in pituitary tumors. 1141 75

Peptidylglycine alpha-amidating monooxygenase (PAM), an integral membrane protein essential for the biosynthesis of amidated peptides, was used to assess the role of cytosolic acidic clusters in trafficking to regulated secretory granules. Casein kinase II phosphorylates Ser(949) and Thr(946) of PAM, generating a short, cytosolic acidic cluster. P-CIP2, a protein kinase identified by its ability to interact with several juxtamembrane determinants in the PAM cytosolic domain, also phosphorylates Ser(949). Antibody specific for phospho-Ser(949)-PAM-CD demonstrates that a small fraction of the PAM-1 localized to the perinuclear region bears this modification. Pituitary cell lines expressing PAM-1 mutants that mimic (TS/DD) or prevent (TS/AA) phosphorylation at these sites were studied. PAM-1 TS/AA yields a lumenal monooxygenase domain that enters secretory granules inefficiently and is rapidly degraded. In contrast, PAM-1 TS/DD is routed to regulated secretory granules more efficiently than wild-type PAM-1 and monooxygenase release is more responsive to secretagogue. Furthermore, this acidic cluster affects exit of internalized PAM-antibody complexes from late endosomes; internalized PAM-1 TS/DD accumulates in a late endocytic compartment instead of the trans-Golgi network. The increased ability of solubilized PAM-1 TS/DD to aggregate at neutral pH may play an important role in its altered trafficking.
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PMID:Access of a membrane protein to secretory granules is facilitated by phosphorylation. 1152 14

Pituitary gonadotropins mediate part of their effects on ovarian function via local hormones and growth factors produced by granulosa cells. Activins and inhibins are among these factors, and they have often opposite effects on various components of the reproductive system. The purpose of this study was to investigate the regulation of ovarian activin A secretion using cultured human ovarian granulosa-luteal cells as a model. The granulosa-luteal cells, obtained from women taking part in an in vitro fertilization program, were cultured and treated with FSH, LH, 8-bromo cAMP (8-BrcAMP, a protein kinase A activator) and 12-O-tetradecanoyl phorbol-13-acetate (TPA, a protein kinase C activator). Conditioned cell culture media were analyzed for activin A, inhibin A and progesterone concentrations with specific enzyme immunoassays. FSH and LH (1-100 IU/l) increased activin A secretion with 24 h of treatment (to 132% and 253% of control respectively; P<0.05 for both), but their effects were inhibitory in 48-h treatments (26% and 16% decreases respectively; P<0.05 for both). In the same experiments, FSH and LH increased inhibin A and progesterone secretion after both 24 and 48 h of treatment. 8-BrcAMP (0.1-100 muM) increased activin A in 24- and 48-h experiments (to 206% and 148% of control respectively; P<0.01 for both). Inhibin A and progesterone secretion were stimulated by 8-BrcAMP time- and dose-dependently. TPA increased activin A secretion dose-dependently (0.1-100 ng/ml) in both 24- and 48-h experiments. At 100 ng/ml concentration, it increased activin A up to 61-fold and inhibin A up to 16-fold of control in 24-h experiments. We conclude that gonadotropins regulate immunoreactive activin A secretion biphasically in cultured human granulosa-luteal cells: initial stimulation is followed by inhibition. In contrast, gonadotropins increase inhibin A and progesterone secretion continuously. Consequently, continuing gonadotropin stimulation leads to a decreasing activin:inhibin ratio, which may have a significant role in the local fine-tuning of ovarian steroidogenesis.
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PMID:Biphasic regulation of activin A secretion by gonadotropins in cultured human ovarian granulosa-luteal cells leads to decreasing activin:inhibin ratios during continuing gonadotropin stimulation. 1187 4


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