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)

Ethanol withdrawal (EW) produces substantial neurotoxic effects, whereas estrogen is neuroprotective. Given observations that both human and nonhuman female subjects often show less impairment following EW, it is reasonable to hypothesize that estrogens may protect females from the neurotoxic effects of ethanol. This article is based on the assumption that the behavioral deficits seen following EW are produced in part by neuronal death triggered by oxidative insults produced by EW. The EW leads to activation of protein kinase C, especially PKCepsilon, which subsequently triggers apoptotic downstream events such as phosphorylation of nuclear factor-kappaB (NFkappaB) complex. On phosphorylation, active NFkappaB translocates to the nucleus, binds to DNA, and activates caspases, which trigger DNA fragmentation and apoptosis. In contrast, estrogens are antioxidant, inhibit overexpression of PKCepsilon, and suppress expression of NFkappaB and caspases. Estrogen treatment reduces the behavioral deficits seen during EW and attenuates molecular signals of apoptosis. The effects of ethanol and estrogen on each step in the signaling cascade from ethanol exposure to apoptosis are reviewed, and potential mechanisms by which estrogen could produce neuronal protection against the neurotoxicity produced by EW are identified. These studies serve as a guide for continuing research into the mechanisms of the neuroprotective effects of estrogen during EW and for the development of potential estrogen-based treatments for male and female alcoholics.
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PMID:Estrogen neuroprotection against the neurotoxic effects of ethanol withdrawal: potential mechanisms. 1561 21

Estrogen exerts many of its receptor-mediated neuroprotective functions through the activation of various intracellular signal transduction pathways including the mitogen activating protein kinase (MAPK), phospho inositol-3 kinase and protein kinase C pathways. Here we have used a hippocampal slice culture model of kainic acid-induced neurotoxic cell death to show that estrogen can protect against oxidative cell death. We have previously shown that MAPK and glycogen synthase kinase-3beta (GSK-3beta) are involved in the cell death/cell survival induced by kainic acid. In this model and other cellular and in vivo models we have shown that estrogen can also cause the phosphorylation and hence inactivation of GSK-3beta, a known mediator of neuronal cell death. The effect of estrogen on GSK-3beta activity is estrogen receptor mediated. Further, this estrogen/GSK-3beta interaction may have functional consequences in cellular models of some key pathogenic pathways associated with Alzheimer's disease. More specifically, estrogen affects the basal levels of tau phosphorylation at a site known to be phosphorylated by GSK-3beta. Taken together, these data indicate a novel molecular and functional link between estrogen and GSK-3beta and may have implications for estrogen receptor modulation as a target for the prevention of neurodegenerative disorders.
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PMID:Glycogen synthase kinase 3beta links neuroprotection by 17beta-estradiol to key Alzheimer processes. 1583 20

Estrogen has demonstrated neuroprotective properties, which may underlie the observed preventive effect of estrogen-based hormone therapy (HT) against the development of neurodegenerative disorders such as Alzheimer's disease. Deleterious side effects of HT have increased efforts to develop safer compounds that selectively reproduce beneficial estrogen actions. Recently, 4-estren-3 alpha,17 beta-diol (estren) was identified as having estrogen agonist properties in bone, without significantly stimulating growth of reproductive tissues. Here, we examined whether estren parallels the neuroprotective actions of estrogen against beta-amyloid (A beta) in cultured cerebrocortical neurons. Estren increased neuronal viability to a similar extent to that observed with 17 beta-estradiol (E2) and 17 alpha-estradiol. As we previously reported for E2, estren rapidly increased PKC activity, and PKC inhibition prevented estren neuroprotection. In contrast, the estrogen receptor antagonist ICI 182,780 blocked E2, but not estren neuroprotection. Our results indicate that estren-induced activation of rapid cell signaling pathways protects cultured neurons from A beta toxicity.
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PMID:The synthetic estrogen 4-estren-3 alpha,17 beta-diol (estren) induces estrogen-like neuroprotection. 1583 89

Estrogen is a ligand for the estrogen receptor (ER), which on binding 17beta-estradiol, functions as a ligand-activated transcription factor and regulates the transcription of target genes. This is the slow genomic mode of action. However, rapid non-genomic actions of estrogen also exist at the cell membrane. Using a novel two-pulse paradigm in which the first pulse rapidly initiates non-genomic actions using a membrane-limited estrogen conjugate (E-BSA), while the second pulse promotes genomic transcription from a consensus estrogen response element (ERE), we have demonstrated that rapid actions of estrogen potentiate the slower transcriptional response from an ERE-reporter in neuroblastoma cells. Since rapid actions of estrogen activate kinases, we used selective inhibitors in the two-pulse paradigm to determine the intracellular signaling cascades important in such potentiation. Inhibition of protein kinase A (PKA), PKC, mitogen activated protein kinase (MAPK) or phosphatidylinositol 3-OH kinase (PI-3K) in the first pulse decreases potentiation of transcription. Also, our data with both dominant negative and constitutive mutants of Galpha subunits show that Galpha(q) initiates the rapid signaling cascade at the membrane in SK-N-BE(2)C neuroblastoma cells. We discuss two models of multiple kinase activation at the membrane Pulses of estrogen induce lordosis behavior in female rats. Infusion of E-BSA into the ventromedial hypothalamus followed by 17beta-estradiol in the second pulse could induce lordosis behavior, demonstrating the applicability of this paradigm in vivo. A model where non-genomic actions of estrogen couple to genomic actions unites both aspects of hormone action.
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PMID:Integration of steroid hormone initiated membrane action to genomic function in the brain. 1586 22

Some estrogenic compounds are reported to cause testicular disorders in humans and/or experimental animals by direct action on Leydig cells. In carcinogenesis and normal development, gap junctional intercellular communication (GJIC) plays an essential role in maintaining homeostasis. In this study, we examine the effects of diethylstilbestrol (DES, a synthetic estrogen), 17beta-estradiol (E(2), a natural estrogen), and genistein (GEN, a phytoestrogen) on GJIC between mouse Leydig TM3 cells using Lucifer yellow microinjection. The three compounds tested produced GJIC inhibition in the TM3 cells after 24 h. Gradually, 10 microM DES began to inhibit GJIC for 24 h and this effect was observed until 72 h. On the other hand, both 20 microM E(2) and 25 microM GEN rapidly inhibited GJIC in 6 h and 2 h, respectively. The effects continued until 24 h, but weakened by 72 h. Furthermore, a combined effect at microM level between DES and E(2) on GJIC inhibition was observed, but not between GEN and E(2). DES and E(2) showed GJIC inhibition at low dose levels (nearly physiological estrogen levels) after 72 h, but GEN did not. DES-induced GJIC inhibition at 10 pM and 10 microM was completely counteracted by ICI 182,780 (ICl), an estrogen receptor antagonist. On the other hand, the inhibitory effects on GJIC with E(2) (10 pM and 20 microM) and GEN (25 microM) were partially blocked by ICI or calphostin C, a protein kinase C (PKC) inhibitor, and were completely blocked by the combination of ICI and calphostin C. These results demonstrate that DES inhibits GJIC between Leydig cells via the estrogen receptor (ER), and that E(2) and GEN inhibit GJIC via ER and PKC. These estrogenic compounds may have different individual non-genotoxic mechanism including PKC pathway on testicular carcinogenesis or development.
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PMID:Estrogenic compounds inhibit gap junctional intercellular communication in mouse Leydig TM3 cells. 1619 72

Both male and female rat growth plate cartilage cells possess estrogen receptors (ERs), but 17beta-estradiol (E(2)) activates protein kinase C (PKC) and PKC-dependent biological responses to E(2) only in cells from female animals. PKC signaling can elicit genomic responses via mitogen activated protein kinase (MAPK) and E(2) has been shown to activate ERK MAPK in many cells, suggesting that MAPK may play a role in growth plate chondrocytes as well. We tested if E(2) increases MAPK activity and if so, whether the response is limited to female cells, if it is PKC-dependent, and if the mechanism involves traditional ER pathways. We also determined the contribution of MAPK to the biological response of growth plate chondrocytes and assessed the relative contributions of ERK, p38 and JNK MAPKs. Female rat costochondral cartilage cells were treated with E(2) and MAPK-specific activity determined in cell layer lysates. The mechanism of MAPK activation was determined by treating the cells with E(2) conjugated to bovine serum albumin (E(2)-BSA) to assess if membrane receptors were involved; stereospecificity was determined using 17alpha-estradiol; PKC and phospholipase C (PLC) dependence was determined using specific inhibitors; and the ER agonist diethylstilbestrol, the ER antagonist ICI 182780, and tamoxifen were used to assess the role of traditional ER pathways. E(2) regulation of ERK1/2 MAPK was assessed and the relative roles of ERK1/2, p38 and JNK MAPKs determined using specific inhibitors. E(2) caused a rapid dose-dependent activation of MAPK that was greatest in cells treated for 9 min with 10(-9) M hormone; activity remained elevated for 3 h. E(2)'s effect on MAPK was stereospecific and comparable to that of E(2)-BSA. It was insensitive to DES and ICI 182780, dependent on PKC and PLC, blocked by tamoxifen and it did not require gene transcription or translation. E(2) had no effect on ERK1 or ERK2 mRNA or protein but it caused a rapid phosphorylation of ERK1/2 at 9 min. Inhibition of ERK1/2 and p38 MAPK reduced the stimulatory effects of E(2) on alkaline phosphatase activity and [(35)S]-sulfate incorporation. These results suggest that E(2) regulates MAPK through a sex-specific membrane-mediated mechanism that does not involve cytosolic ERs in a traditional sense and that ERK1/2 and p38 mediate the downstream biological effects of the hormone.
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PMID:Sex-specific regulation of growth plate chondrocytes by estrogen is via multiple MAP kinase signaling pathways. 1671 47

Small-fiber painful peripheral neuropathy, a complication of chronic ethanol ingestion, is more severe in women. In the present study, we have replicated this clinical finding in the rat and evaluated for a role of estrogen and second messenger signaling pathways. The alcohol diet (6.5% ethanol volume:volume in Lieber-DeCarli formula) induced hyperalgesia with more rapid onset and severity in females. Following ovariectomy, alcohol failed to induce hyperalgesia in female rats, well past its time to onset in gonad intact males and females. Estrogen replacement reinstated alcohol neuropathy in the female rat. The protein kinase A (PKA) inhibitor (Walsh inhibitor peptide, WIPTIDE) only attenuated alcohol-induced hyperalgesia in female rats. Inhibitors of protein kinase Cepsilon (PKCepsilon-I) and extracellular-signal related kinase (ERK) 1/2 (2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (U0126)) attenuated hyperalgesia in males and females, however the degree of attenuation produced by PKCepsilon-I was much greater in females. In conclusion, estrogen plays an important role in the expression of pain associated with alcohol neuropathy in the female rat. In contrast to inflammatory hyperalgesia, in which only the contribution of PKCepsilon signaling is sexually dimorphic, in alcohol neuropathy PKA as well as PKCepsilon signaling is highly sexually dimorphic.
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PMID:Severity of alcohol-induced painful peripheral neuropathy in female rats: role of estrogen and protein kinase (A and Cepsilon). 1720 74

The estrogen sex steroid 17beta-estradiol rapidly inhibits secretagogue-stimulated cAMP-dependent Cl(-) secretion in the female rat distal colonic crypt by the inhibition of basolateral K(+) channels. In Ussing chamber studies, both the anti-secretory response and inhibition of basolateral K(+) current was shown to be attenuated by pretreatment with rottlerin, a PKCdelta-specific inhibitor. In whole cell patch-clamp analysis, 17beta-estradiol inhibited a chromanol 293B-sensitive KCNQ1 channel current in isolated female rat distal colonic crypts. Estrogen had no effect on KCNQ1 channel currents in colonic crypts isolated from male rats. Female distal colonic crypts expressed a significantly higher amount of PKCdelta in comparison to male tissue. PKCdelta and PKA were activated at 5 min in response to 17beta-estradiol in female distal colonic crypts only. Both PKCdelta- and PKA-associated with the KCNQ1 channel in response to 17beta-estradiol in female distal colonic crypts, and no associations were observed in crypts from males. PKA activation, association with KCNQ1, and phosphorylation of the channel were regulated by PKCdelta as the responses were blocked by pretreatment with rottlerin. Taken together, our experiments have identified the molecular targets underlying the anti-secretory response to estrogen involving the inhibition of KCNQ1 channel activity via PKCdelta- and PKA-dependent signaling pathways. This is a novel gender-specific mechanism of regulation of an ion channel by estrogen. The anti-secretory response described in this study provides molecular insights whereby estrogen causes fluid retention effects in the female during periods of high circulating plasma estrogen levels.
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PMID:Female gender-specific inhibition of KCNQ1 channels and chloride secretion by 17beta-estradiol in rat distal colonic crypts. 1755 70

Estrogen affects the electrophysiological properties of a number of hypothalamic neurons by modulating K(+) channels via rapid membrane actions and/or changes in gene expression. The interaction between these pathways (membrane vs. transcription) ultimately determines the effects of estrogen on hypothalamic functions. Using suppression subtractive hybridization, we produced a cDNA library of estrogen-regulated, brain-specific guinea pig genes, which included subunits from three prominent K+ channels (KCNQ5, Kir2.4, Kv4.1, and Kvbeta(1)) and signaling molecules that impact channel function including phosphatidylinositol 3-kinase (PI3K), protein kinase Cepsilon (PKCepsilon), cAMP-dependent protein kinase (PKA), A-kinase anchor protein (AKAP), phospholipase C (PLC), and calmodulin. Based on these findings, we dissected the arcuate nucleus from ovariectomized guinea pigs treated with estradiol benzoate (EB) or vehicle and analyzed mRNA expression using quantitative real-time PCR. We found that EB significantly increased the expression of KCNQ5 and Kv4.1 and decreased expression of KCNQ3 and AKAP in the rostral arcuate. In the caudal arcuate, EB increased KCNQ5, Kir2.4, Kv4.1, calmodulin, PKCepsilon, PLCbeta(4), and PI3Kp55gamma expression and decreased Kvbeta(1). The effects of estrogen could be mediated by estrogen receptor-alpha, which we found to be highly expressed in the guinea pig arcuate nucleus and, in particular, proopiomelanocortin neurons. In addition, single-cell RT-PCR analysis revealed that about 50% of proopiomelanocortin and neuropeptide Y neurons expressed KCNQ5, about 40% expressed Kir2.4, and about 60% expressed Kv4.1. Therefore, it is evident that the diverse effects of estrogen on arcuate neurons are mediated in part by regulation of K(+) channel expression, which has the potential to affect profoundly neuronal excitability and homeostatic functions, especially when coupled with the rapid effects of estrogen on K(+) channel function.
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PMID:Estrogen regulation of genes important for K+ channel signaling in the arcuate nucleus. 1759 23

Estrogen is a known immunomodulator with pleiotropic effects on macrophage function that partly accounts for the gender bias observed in numerous autoimmune, cardiovascular, and neurodegenerative disorders. The effect of estrogen on the survival of human macrophages is largely unknown, and in this study we demonstrate that 17beta-estradiol (E2) provokes a death response in human THP-1 macrophages by initiating Bax translocation from cytosol to the mitochondria; however, a concomitant up-regulation of Bcl-2 creates a Bax to Bcl-2 ratio favorable for Bcl-2, thus ensuring cell survival. Both Bcl-2 up-regulation and Bax translocation are estrogen receptor-dependent events; however, Bcl-2 augmentation but not Bax translocation is dependent on Ca(2+) increase, activation of protein kinase C, and ERK phosphorylation. This estrogen-induced Bcl-2 increase is crucial for the survival of THP-1 macrophages as well as that of human peripheral blood monocyte-derived macrophages, which is evident from E2-induced cell death under small interfering RNA-mediated Bcl-2 knockdown conditions. Hence, this study demonstrates that E2-induced Bcl-2 up-regulation is a homeostatic survival mechanism necessary for the manifestation of immunomodulatory effect of estrogen on human macrophages.
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PMID:Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. 1767 94


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