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)

Estradiol prevents neuronal cell death through the activation of cell survival signals and the inhibition of apoptotic signals. This study investigated whether estradiol modulates the anti-apoptotic signal through the activation of Raf-MEK-ERK and its downstream targets, including 90 ribosomal S6 kinase (p90RSK) and Bad. Adult female rats were ovariectomied and treated with estradiol prior to middle cerebral artery occlusion (MCAO). Brains were collected 24h after MCAO and infarct volumes were analyzed. We confirmed that estradiol significantly reduces infarct volume and decreases the positive cells of TUNEL staining in the cerebral cortex. Estradiol prevents the injury-induced decrease of Raf-1, MEK1/2, and ERK1/2 phosphorylation. Also, it inhibits the injury-induced decrease of p90RSK and Bad phosphorylation. Further, in the presence of estradiol, the interaction of phospho-Bad and 14-3-3 increased, compared with that of oil-treated animals. Our findings suggest that estradiol prevents cell death due to brain injury and that Raf-MEK-ERK cascade activation and its downstream targets, p90RSK, Bad phosphorylation by estradiol mediated these protective effects.
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PMID:Estradiol prevents the injury-induced decrease of 90 ribosomal S6 kinase (p90RSK) and Bad phosphorylation. 1719 35

The aim of these in vitro experiments was (1) to examine the effects of ghrelin on the basic functions of ovarian cells (proliferation, apoptosis, secretory activity); (2) to determine the possible involvement of the GHS-R1a receptor and PKA- and MAPK-dependent post-receptor intracellular signalling cascades; (3) to identify the active part of the 28-amino acid molecule responsible for the effects of ghrelin on ovarian cells. We compared the effect of full-length ghrelin 1-28, a synthetic activator of GHS-R1a, GHRP6, and ghrelin molecular fragments 1-18 and 1-5 on cultured chicken ovarian cells. Indices of cell apoptosis (expression of the apoptotic peptide bax and the anti-apoptotic peptide bcl-2), proliferation (expression of proliferation-associated peptide PCNA), and expression of protein kinases (PKA and MAPK) within ovarian granulosa cells were analysed by immunocytochemistry. The secretion of progesterone (P(4)), testosterone (T), estradiol (E(2)) and arginine-vasotocin (AVT) by isolated ovarian follicular fragments was evaluated by RIA/EIA. It was observed that accumulation of bax was increased by ghrelin 1-28, GHRP6 and ghrelin 1-18, but not by ghrelin 1-5. Expression of bcl-2 was suppressed by addition of ghrelin 1-28, GHRP6 and ghrelin 1-5, but promoted by ghrelin 1-18. The occurrence of PCNA was reduced by ghrelin 1-28, GHRP6, ghrelin 1-18 and ghrelin 1-5. An increase in the expression of MAPK/ERK1, 2 was observed after addition of ghrelin 1-28, GHRP6 and ghrelin 1-18, but not ghrelin 1-5. The accumulation of PKA decreased after treatment with ghrelin 1-28 and increased after treatment with GHRP6 and ghrelin 1-18 but not ghrelin 1-5. Secretion of P(4) by ovarian follicular fragments was decreased after addition of ghrelin 1-28 or ghrelin 1-5 but stimulated by GHRP6 and ghrelin 1-18. Testosterone secretion was inhibited by ghrelins 1-28 and 1-18, but not by GHRP6 or ghrelin 1-5. Estradiol secretion was reduced after treatment with ghrelin 1-28 but stimulated by ghrelins 1-18 and 1-5; GHRP6 had no effect. AVT secretion was stimulated by ghrelin 1-28, GHRP6 and ghrelin 1-18, but inhibited by ghrelin 1-5. The comparison of the effects of the four ghrelin analogues on nine parameters of ovarian cells suggest (1) a direct effect of ghrelin on basic ovarian functions-apoptosis, proliferation, steroid and peptide hormone secretion; (2) that the majority of these effects can be mediated through GHS-R1a receptors; (3) an effect of ghrelin on MAPK- and PKA-dependent intracellular mechanisms, which can potentially mediate the action of ghrelin at the post-receptor level; (4) that ghrelin residues 5-18 may be responsible for the major effects of ghrelin on the avian ovary.
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PMID:Effects of ghrelin and its analogues on chicken ovarian granulosa cells. 1720 55

Estradiol treatment produced significant increase of total 11-hydroxycorticosteroids level in the blood of intact and castrated rats. Activity of protein kinase A increased in the cytosol and membrane fraction of adrenocorticocytes of intact and orchiectomized rats after estradiol influence. Activity of protein kinase C significantly raised in the cytosol and membrane fraction of adrenocortical cells in all investigated groups. Our results suggest that cAMP-dependent protein kinase A and protein kinase C mediate estradiol effects in adrenal cortex.
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PMID:[Effects of estradiol on synthesis of corticosteroids, protein kinase A and C activity in the adrenal cortex of intact and orchiectomized rats]. 1733 20

Pain symptoms in several chronic pain disorders in women, including irritable bowel syndrome, fluctuate with the menstrual cycle suggesting a gonadal hormone component. In female rats, estrogens modulate visceral sensitivity although the underlying mechanism(s) are unknown. In the present study the effects of 17-beta estradiol on N-methyl-D-aspartate (NMDA) receptor signaling of colorectal nociceptive processing in the spinal cord were examined. Estrogen receptor alpha and the NR1 subunit of the NMDA receptor are co-expressed in dorsal horn neurons, supporting a direct action of estradiol on NMDA receptors. Intrathecal administration of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response with greater potency in ovariectomized (OVx) rats compared to OVx with estradiol replacement (E2) rats. Estradiol significantly increased protein expression of NR1 in the lumbosacral spinal cord compared to OVx rats. Colorectal distention significantly increased phosphorylation of NR1ser-897, a PKA phosphorylation site on the NR1 subunit in E2, but not OVx rats. Intrathecal administration of a PKA inhibitor significantly attenuated the visceromotor response, decreased NR1 phosphorylation and increased the potency of APV to attenuate the visceromotor response compared to vehicle-treated E2 rats. These data suggest that estradiol increases spinal processing of visceral nociception by increasing NMDA receptor NR1 subunit expression and increasing site-specific receptor phosphorylation on the NR1 subunit contributing to an increase in NMDA receptor activity.
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PMID:Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat. 1806 1

We tested the hypothesis that GnRH, PGE2 and db-cAMP act via the nitric oxide (NO)-cGMP and MAPK pathways to facilitate estrous behavior (lordosis and proceptivity) in estradiol-primed female rats. Estradiol-primed rats received intracerebroventricular (icv) infusions of pharmacological antagonists of NO synthase (L-NAME), NO-dependent soluble guanylyl cyclase (ODQ), protein kinase G (KT5823), or the ERK1/2 inhibitor PD98059 15 min before icv administration of 50 ng of GnRH, 1 microg of PGE2 or 1 microg of db-cAMP. Icv infusions of GnRH, PGE2 and db-cAMP enhanced estrous behavior at 1 and 2 h after drug administration. Both L-NAME and ODQ blocked the estrous behavior induced by GnRH, PGE2 and db-cAMP at some of the times tested. The protein kinase G inhibitor KT5823 reduced PGE2 and db-cAMP facilitation of estrous behavior but did not affect the behavioral response to GnRH. In contrast, PD98059 blocked the estrous behavior induced by all three compounds. These data support the hypothesis that the NO-cGMP and ERK/MAPK pathways are involved in the lordosis and proceptive behaviors induced by GnRH, PGE2 and db-cAMP. However, cGMP mediation of GnRH-facilitated estrous behavior is independent of protein kinase G.
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PMID:Nitric oxide and ERK/MAPK mediation of estrous behavior induced by GnRH, PGE2 and db-cAMP in rats. 1916 55

The hypothalamic-pituitary-adrenal (HPA) axis is activated under various stressors. Corticotropin-releasing factor (CRF) plays a central role in controlling stress response, and regulating the HPA axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN), stimulates adrenocorticotropic hormone (ACTH) production via CRF receptor type 1 (CRF(1) receptor) from the corticotrophs of the anterior pituitary (AP). Cyclic AMP (cAMP)-protein kinase A (PKA) pathway takes a main role in stimulating CRF gene transcription. Forskolin and pituitary adenylate cyclase-activating polypeptide (PACAP) stimulate adenylate cyclase, intracellular cAMP production, and then CRF and arginine vasopressin (AVP) gene expression in hypothalamic 4B cells. Interleukin (IL)-6, produced in the PVN, both directly and indirectly stimulates CRF and AVP gene expression. Estradiol may enhance the activation of CRF gene expression in response to stress. The HPA axis is regulated by a negative feedback mechanism, because glucocorticoids inhibit both CRF production in the hypothalamic PVN and ACTH production in the pituitary. Hypothalamic parvocellular neurons in the PVN are known to express glucocorticoid receptors, and glucocorticoids are able to regulate CRF gene transcription and expression levels directly in the PVN. Glucocorticoids-dependent repression of cAMP-stimulated CRF promoter activity is mainly localized to promoter sequences between -278 and -233 bp. Both negative glucocorticoid regulatory element (nGRE) and serum response element (SRE) are involved in the repression of the CRF gene in the hypothalamic cells.
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PMID:Regulatory mechanisms underlying corticotropin-releasing factor gene expression in the hypothalamus. 1935 56

Gonadotropin-releasing hormone (GnRH) neurons are critical to controlling fertility. In vivo, estradiol can inhibit or stimulate GnRH release depending on concentration and physiological state. We examined rapid, nongenomic effects of estradiol. Whole-cell recordings were made of GnRH neurons in brain slices from ovariectomized mice with ionotropic GABA and glutamate receptors blocked. Estradiol was bath applied and measurements completed within 15 min. Estradiol from high physiological (preovulatory) concentrations (100 pm) to 100 nm enhanced action potential firing, reduced afterhyperpolarizing potential (AHP) and increased slow afterdepolarization amplitudes (ADP), and reduced I(AHP) and enhanced I(ADP). The reduction of I(AHP) was occluded by previous blockade of calcium-activated potassium channels. These effects were mimicked by an estrogen receptor (ER) beta-specific agonist and were blocked by the classical receptor antagonist ICI182780. ERalpha or GPR30 agonists had no effect. The acute stimulatory effect of high physiological estradiol on firing rate was dependent on signaling via protein kinase A. In contrast, low physiological levels of estradiol (10 pm) did not affect intrinsic properties. Without blockade of ionotropic GABA and glutamate receptors, however, 10 pm estradiol reduced firing of GnRH neurons; this was mimicked by an ERalpha agonist. ERalpha agonists reduced the frequency of GABA transmission to GnRH neurons; GABA can excite to these cells. In contrast, ERbeta agonists increased GABA transmission and postsynaptic response. These data suggest rapid intrinsic and network modulation of GnRH neurons by estradiol is dependent on both dose and receptor subtype. In cooperation with genomic actions, nongenomic effects may play a role in feedback regulation of GnRH secretion.
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PMID:Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype. 1940 28

Glutathione (GSH), the most abundant intracellular nonprotein thiol, is critical for many cellular functions. The rate-limiting step in GSH synthesis is catalyzed by glutamate cysteine ligase (GCL), a heterodimer composed of a catalytic (GCLC) and a modifier (GCLM) subunit. The tissue-specific regulation of GSH synthesis is poorly understood. We showed previously that gonadotropin hormones regulate ovarian GSH synthesis. In the present study, we sought to clarify the ovarian cell type-specific effects of follicle-stimulating hormone (FSH) and estradiol on GSH synthesis. Immature female rats were treated with estradiol to stimulate development of small antral follicles. Granulosa cells (GCs) from these follicles or whole follicles were cultured in serum-free media, with or without FSH and 17beta-estradiol. The GSH and GCLC protein and mRNA levels increased in GCs treated with FSH alone. The effects of FSH on GCLC and GCLM protein and mRNA levels, GCL enzymatic activity, and GSH concentrations in GCs were significantly enhanced by the addition of estradiol. Estradiol alone had no effects on GSH. Dibromo-cAMP mimicked and protein kinase A (PKA) inhibitors prevented FSH stimulation of GCL subunit protein levels. In cultured small antral follicles, FSH stimulated estradiol synthesis and robustly increased GCL subunit mRNA and protein levels and GSH concentrations. The GCL subunit mRNA expression increased in both the granulosa cells and theca cells of follicles with FSH stimulation. These data demonstrate that maximal stimulation of GSH synthesis by FSH in granulosa cells and follicles requires estradiol. Without estradiol, FSH causes lesser increases in GCL subunit expression via a PKA-dependent pathway.
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PMID:Follicle-stimulating hormone and estradiol interact to stimulate glutathione synthesis in rat ovarian follicles and granulosa cells. 1951 19

Recent studies suggest that the rapid and nongenomic effects of estradiol may be mediated through the G protein-coupled receptor dubbed GPR30 receptor. The present study examines the role of GPR30 versus a classical estrogen receptor (ERalpha) in mediating the growth regulatory effects of estradiol. GPR30 is readily detectable in freshly isolated vascular tissue but barely detectable in cultured vascular smooth muscle cells (VSMC). In freshly isolated aortic tissue, estradiol stimulated extracellular signal-regulated kinases (ERK) phosphorylation. In contrast, in cultured VSMC, where GPR30 expression is significantly reduced, estradiol inhibits ERK phosphorylation. Transfer of the genes encoding GPR30 led to estradiol stimulation of ERK phosphorylation, which is opposite the effects of estradiol in the primary culture of VSMCs. Transduction of the mineralocorticoid receptor (MR) had no effect on estradiol effects on ERK. Estradiol-mediated stimulation of ERK subsequent to heterologous GPR30 expression was pertussis toxin sensitive and phosphoinositide 3-kinase (PI3 kinase) dependent; under these conditions, estradiol also inhibited protein kinase A (PKA). In contrast, in the absence of GPR30 expression in cultured VSMC, estradiol stimulated PKA activity and inhibited ERK phosphorylation. To determine the functional effect of GPR30 (vs. estrogen receptor expression), we assessed estradiol-mediated apoptosis. In the absence of GPR30 expression, estradiol inhibited apoptosis. This effect was enhanced with ERalpha expression. In contrast, with GPR30 expression, estradiol stimulated apoptosis in an ERK-dependent manner. Thus the effect of estradiol on vascular smooth muscle cell apoptosis is likely dependent on the balance between ER-mediated PKA activation and GPR30-mediated PKA inhibition and PI3 kinase activation. Taken together, we postulate that modulation of GPR30 expression or activity may be an important determinant of the effects of estradiol in the vasculature.
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PMID:Estradiol-mediated ERK phosphorylation and apoptosis in vascular smooth muscle cells requires GPR 30. 1974 Nov 98

We have previously reported that estradiol can protect heart mitochondria from the ischemia-induced mitochondrial permeability transition pore-related release of cytochrome c and subsequent apoptosis. In this study we investigated whether the effect of 17-beta-estradiol on ischemia-induced mitochondrial dysfunctions and apoptosis is mediated by activation of signaling protein kinases in a Langendorff-perfused rat heart model of stop-flow ischemia. We found that pre-perfusion of non-ischemic hearts with 100nM estradiol increased the resistance of subsequently isolated mitochondria to the calcium-induced opening of mitochondrial permeability transition pore and this was mediated by protein kinase G. Loading of the hearts with estradiol prevented ischemia-induced loss of cytochrome c from mitochondria and respiratory inhibition and these effects were reversed in the presence of the inhibitor of Akt kinase, NO synthase inhibitor L-NAME, guanylyl cyclase inhibitor ODQ and protein kinase G inhibitor KT5823. Estradiol prevented ischemia-induced activation of caspases and this was also reversed by KT5823. These findings suggest that estradiol may protect the heart against ischemia-induced injury activating the signaling cascade which involves Akt kinase, NO synthase, guanylyl cyclase and protein kinase G, and results in blockage of mitochondrial permeability transition pore-induced release of cytochrome c from mitochondria, respiratory inhibition and activation of caspases.
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PMID:Estradiol-induced protection against ischemia-induced heart mitochondrial damage and caspase activation is mediated by protein kinase G. 2038 50


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