Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of lead on the signal transduction pathways that may be involved in the release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus have not been well defined. Using the GT1-7 cell line, an in vitro model for GnRH-secreting neurons, we examined signal transduction pathways directly affected by lead. We found that lead-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2), as well as p90RSK and cAMP response element-binding protein (CREB), but did not induce IkappaB degradation. MEK1/2 inhibitor (PD98059) suppressed lead-induced ERK and p90RSK activation. Neither PKC inhibitors (Go6983, Go6976) nor CaMKII inhibitor (KN-62) had a pronounced effect on lead-induced ERK1 and ERK2 phosphorylation. However, MEK1/2 inhibitor, CaMKII inhibitor, and PKC inhibitor significantly suppressed lead-induced CREB phosphorylation. These results indicate that lead-activated PKC, CaMKII and MEK/ERK/p90RSK pathways simultaneously, all of which contributed to CREB phosphorylation. Our results also indicate that lead-induced p90RSK and CREB activation does not alter expression of early response genes like c-fos. We conclude that lead activates PKC, CaMKII or MEK-ERK-p90RSK pathways in GT1-7 cells, leading to CREB phosphorylation and modulation of gene expression.
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PMID:Lead-induced cell signaling cascades in GT1-7 cells. 1283 8

Luteinizing hormone (LH) consists of alpha- and beta-subunits, and synthesis and secretion of LH are regulated by gonadotropin-releasing hormone (GnRH). In order to examine the molecular mechanisms by which GnRH regulates LH secretion, we transfected alphaT3-1 cells with rat LHbeta-subunit cDNA under the control of a constitutive promoter and established a stable cell line of LH2 cells which secreted LH in response to GnRH. Pulsatile and continuous GnRH pretreatments increased gene expression of the alpha-subunit and synthesis of LH, and enhanced the LH secretion by brief treatments with GnRH and 56 mM KCl. The LH secretions were partially blocked by elimination of extracellular Ca2+. GnRH-induced LH secretion was completely inhibited by calphostin C (a protein kinase C inhibitor) and 1 microM wortmannin. In contrast to the GnRH induction, high K+-induced LH secretion was inhibited by KN93, a Ca2+/calmodulin-dependent protein kinase II inhibitor, as well as by 1 microM wortmannin. We also confirmed that activation of cAMP-pathway induced LH secretion, but activation of mitogen-activated protein (MAP) kinase pathway was not involved in LH secretion. These results suggest that GnRH directly regulates LH secretion as well as LHbeta-subunit synthesis, and that LH2 cells are a useful model for the study of LH secretion induced by several secretagogues.
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PMID:Characterization of alphaT3-1 cells stably transfected with luteininzing hormone beta-subunit complementary deoxyribonucleic acid. 1294 Apr 64

In the goldfish, norepinephrine (NE) inhibits growth hormone (GH) secretion through activation of pituitary alpha(2)-adrenergic receptors. Interestingly, a GH rebound is observed after NE withdrawal, which can be markedly enhanced by prior exposure to gonadotropin-releasing hormone (GnRH). Here we examined the mechanisms responsible for GnRH potentiation of this "postinhibition" GH rebound. In goldfish pituitary cells, alpha(2)-adrenergic stimulation suppressed both basal and GnRH-induced GH mRNA expression, suggesting that a rise in GH synthesis induced by GnRH did not contribute to its potentiating effect. Using a column perifusion approach, GnRH given during NE treatment consistently enhanced the GH rebound following NE withdrawal. This potentiating effect was mimicked by activation of PKC and adenylate cyclase (AC) but not by induction of Ca(2+) entry through voltage-sensitive Ca(2+) channels (VSCC). Furthermore, GnRH-potentiated GH rebound could be alleviated by inactivation of PKC, removal of extracellular Ca(2+), blockade of VSCC, and inhibition of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII). Inactivation of AC and PKA, however, was not effective in this regard. These results, as a whole, suggest that GnRH potentiation of GH rebound following NE inhibition is mediated by PKC coupled to Ca(2+) entry through VSCC and subsequent activation of CaMKII. Apparently, the Ca(2+)-dependent cascades are involved in GH secretion during the rebound phase but are not essential for the initiation of GnRH potentiation. Since GnRH has been previously shown to have no effects on cAMP synthesis in goldfish pituitary cells, the involvement of cAMP-dependent mechanisms in GnRH potentiation is rather unlikely.
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PMID:Mechanisms for gonadotropin-releasing hormone potentiation of growth hormone rebound following norepinephrine inhibition in goldfish pituitary cells. 1694 Apr 69

The neurotransmitter gamma-aminobutyric acid (GABA) is an important modulator of gonadotropin-releasing hormone (GnRH), and consequently of reproduction. GABA, acting via ionotropic GABAA receptors, exerts a biphasic effect on GnRH secretion in immortalized GnRH cells. The initial increase in GnRH secretion is triggered by a sharp rise in [Ca2+]i, while the progressive decline of GnRH levels that follows is paralleled by reduced levels of intracellular cAMP. The experiments described here were designed to explore the potential signaling pathways involved in this novel GABAA ionotropic inhibition of cAMP synthesis in GT1-7 cells. Using RT-PCR and real-time PCR, we found that GT1-7 cells express 8 of 9 known membrane adenylyl cyclase (AC) isoforms, including a large proportion of AC3 and AC9, as well as AC5 and AC6, all of which are negatively regulated by increases in [Ca2+]i. In contrast, isoforms of AC that are positively regulated by [Ca2+]i were barely detectable (AC1) or undetectable (AC8). Pharmacological activation of L-type voltage-operated calcium channels with BayK 8644 produced a decrease in [cAMP]i similar to that induced by GABA, while blocking these calcium channels with verapamil reversed the effect of GABA on cAMP synthesis. Furthermore, blocking calcineurin with deltamethrin, FK-506 or cyclosporin A blocked the inhibitory effect of GABA on [cAMP]i, supporting the involvement of AC9 in this effect. In addition, blocking Ca2+/calmodulin-dependent protein kinase II (CamKII) with KN-62 partially reversed the action of GABA, suggesting that AC3 may also be involved in this effect. Finally, GABA increased phosphatase activity in a calcium-dependent manner, an effect blocked by calcineurin inhibitors. Collectively, our results show that the ionotropic action of GABA via the activation of GABAA receptors can decrease AC activity in immortalized GnRH neurons, and that the effect of GABA appears to be mediated by a transient increase in [Ca2+]i followed by activation of calcineurin and CamKII, leading to dephosphorylation of AC9 and phosphorylation of AC3, respectively, and subsequently reducing the synthesis of cAMP.
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PMID:GABA inhibition of cyclic AMP production in immortalized GnRH neurons is mediated by calcineurin-dependent dephosphorylation of adenylyl cyclase 9. 1755 Dec 63