Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of endometriosis with gonadotropin-releasing hormone agonists (GnRH-a) is associated with side effects secondary to the induced hypoestrogenic state. In an effort to ameliorate these symptoms, 10 patients with symptomatic endometriosis self-administered the GnRH-a [D-His6(Imbzl)-Pro9-NET]-GnRH in combination with norethindrone daily for 24 weeks. Painful symptoms were significantly suppressed after therapy (P less than 0.005). Objective review of photographs taken at laparoscopy before and after therapy demonstrated significant reduction of visible implants (P less than 0.005). Vasomotor symptoms were minimized when compared with a group of 16 patients previously treated with GnRH-a alone. Bone mineral density of the distal radius assessed by single photon absorptiometry was not reduced during therapy, although lumbar spine bone density assessed by quantitative computerized tomography was minimally but reversibly reduced. No metabolic derangements were detected. The combination of norethindrone with GnRH-a is a well tolerated and effective means of treating symptomatic endometriosis.
 ...
PMID:The effects of combining norethindrone with a gonadotropin-releasing hormone agonist in the treatment of symptomatic endometriosis. 210 56

Experiments were carried out to investigate the effects of ovariectomy on gonadotropin-releasing hormone (GnRH) messenger RNA (mRNA), proGnRH and GnRH peptide levels in the hypothalamus of female rats. Intact proestrous female rats and female rats, which had been ovariectomized for 2 weeks, were sacrificed at 9.00 h and the preoptic area (POA) and basal hypothalamus (BH) were dissected out and frozen on dry ice. One group of tissues from proestrous control and ovariectomized females were extracted in acetic acid, centrifuged at 13,000 g and the supernatant purified on a C18 column. The purified extract was then radioimmunoassayed for proGnRH, using a specific antiserum to rat proGnRH (ARK-2), and for GnRH using the E1-14 antiserum. Total cellular RNA was isolated from another group of tissues and prepared as Northern blots. Hybridization with 32P-labeled GnRH cRNA was used to detect GnRH mRNA. A third group of proestrous and ovariectomized female rats were perfused, and 50 microns vibratome sections were cut. These were immunostained with proGnRH or GnRH antiserum, followed by in situ hybridization with 35S-labeled GnRH cRNA to detect GnRH mRNA. Based on the histochemical staining, mRNA was colocalized to the cell soma of neurons containing proGnRH and GnRH throughout the POA and BH. Based on the radioimmunoassay, proGnRH levels were 2 times higher in the POA versus the BH, but GnRH levels were 6-7 times higher in the BH. Ovariectomy significantly decreased proGnRH levels in both the POA and BH, while GnRH decreased in the BH. In contrast, quantitative Northern blot analysis demonstrated that ovariectomy had no effect on mRNA levels in the POA and BH. These data indicate that the effects of ovariectomy on proGnRH and GnRH levels are a result of altered translation, posttranslational processing and/or secretion of GnRH.
 ...
PMID:Effects of ovariectomy on GnRH mRNA, proGnRH and GnRH levels in the preoptic hypothalamus of the female rat. 246 86

The authors employed a gonadotropin-releasing hormone agonist (GnRH-a) (D-His6-pro9-NET-GnRH) to treat 19 patients with symptomatic uterine leiomyomata, by daily subcutaneous injections (4 micrograms/kg) for 6 months. After therapy, patients were followed for 6 months without any therapy. Uterine volumes were measured by serial pelvic examinations and pelvic sonography. Measurements of serum estradiol, luteinizing hormone, and follicle-stimulating hormone were used to assess treatment response. Pituitary desensitization and hypoestrogenemia were achieved in all within 8 weeks, and in 18 of 19, hypoestrogenemia was maintained for the duration. Uterine volume at the conclusion of therapy (207.5 +/- 152.7 ml) was significantly reduced in all patients when compared with pretreatment sizes (420.8 +/- 276.4, P less than 0.05). Side effects included hot flashes (78%), vaginal dryness (32%), and transient frontal headaches (55%). All patients reported partial or complete relief from their symptomatic leiomyomata. Uterine volume at the conclusion of follow-up (345.4 +/- 195.7 ml) was greater than at the conclusion of therapy. Menses resumed in all patients within 4 to 8 weeks. In conclusion, GnRH-a therapy does not provide definitive therapy for symptomatic uterine leiomyomata but is effective in reducing the size of leiomyomata as a temporary measure. Gonadotropin-releasing hormone agonist therapy may be useful as an adjunct before myomectomy or hysterectomy and deserves further investigation.
 ...
PMID:Efficacy of a gonadotropin-releasing hormone agonist in the treatment of uterine leiomyomata: long-term follow-up. 249 32

The site of gonadotrophin inhibition in long-term users of injectable contraceptives is still debatable. The pituitary response to LHRH (50 micrograms, I.V.) was assessed in 32 women. Sixteen cases were using either medroxyprogesterone acetate (DMPA; n = 8 150 mg I.M. every three months) or norethisterone enanthate (NET-EN; n = 8, 200 mg every 2 months) for at least 18 months. The remaining cases (n = 16) were normal fertile females not using any hormonal contraceptive (control group). The pituitary response to LHRH injection in both injectable subgroups was nearly identical to that in the control group. Neither the basal levels nor the net increase in gonadotrophins following LHRH injection were significantly different in the study groups from those of the control group. Long-term use of DMPA or NET-EN does not affect the pituitary responsiveness to LHRH injection and the pituitary is not a primary site for ovulation inhibition in these cases.
 ...
PMID:Pituitary response to LHRH in long-term users of injectable contraceptives. 295 67

An antiserum (ARK-1) specific to the gonadotropin-releasing hormone precursor (proGnRH) was produced by immunizing with a synthetic peptide (proGnRH 6-16; Gly-Leu-Arg-Pro-Gly-Gly-Lys-Arg-Asp-Ala-Glu) which bridges the proteolytic cleavage site of proGnRH. When used in the radioimmunoassay, ARK-1 bound 25% of the iodinated 5-16 fragment at a 1:30,000 dilution with a sensitivity of 1 pg/tube. Using immunohistochemical techniques, we observed that in serial and the same sections through the preoptic-basal hypothalamus (POA-BH), the precursor molecule was primarily present in the cell soma, whereas GnRH was found in the cell soma, nerve fibers, and terminals of the same neurons. These data indicate that the processing of proGnRH to biologically active peptides (e.g., GnRH) in the rhesus macaque and the baboon POA-BH primarily occurs in the cell soma.
 ...
PMID:Immunohistochemical demonstration of proGnRH and GnRH in the preoptic-basal hypothalamus of the primate. 330 46

Galanin (GAL) has recently emerged as an important neuroendocrine regulator which participates in the control of several pituitary and hypothalamic hormones. Our earlier observation that GAL stimulates LHRH release from nerve terminals of the median eminence as well as basal LH and LHRH-induced LH secretion from pituitary cells in vitro prompted us to evaluate whether endogenous GAL plays a role in regulation of the physiologically occurring preovulatory surges of gonadotropins and PRL. Proestrous female rats were passively immunized against GAL using a high affinity sheep antirat GAL serum (FMS-FJL 17-5). Animals were implanted during diestrus with indwelling atrial cannulae. On the expected day of proestrus, rats received 1 ml of either normal sheep serum or GAL antiserum (GAL-AS), iv, 1 h before blood sampling started. Blood samples (0.5 ml) were collected at hourly intervals from 1400-2300 h, and plasma levels of LH, FSH, and PRL measured by RIA. At several time intervals after GAL-AS administration, the maximum binding ability of the rat plasma was evaluated using standard saturation assays. High neutralizing levels of immunoglobulins were present throughout the experimental period. GAL passive immunization blunted the LH preovulatory surge by 30%. Although maximum LH levels were unaffected by the treatment, the area under the secretory curve and LH levels at 1700, 1900, and 2000 h were significantly reduced. Conversely, FSH secretion was not significantly altered for either maximum FSH levels or area under the curve. However, FSH levels were significantly diminished in GAL-AS-treated rats at 1700 h. GAL passive immunization selectively reduced the plateau phase of the preovulatory surge of PRL. No significant differences were observed in the initiation of the surge or maximum PRL levels, whereas PRL levels were significantly reduced from 1700 to 2200 h. In addition, the area under the PRL curve was diminished in GAL-AS-treated animals by 40%. In conclusion, our results clearly demonstrate that endogenous GAL is involved in control of the preovulatory surges of LH and PRL without altering the FSH surge. In addition, they provide, for the first time, evidence of an important role for endogenous GAL in the regulation of physiological events leading to ovulation.
 ...
PMID:Endogenous galanin modulates the gonadotropin and prolactin proestrous surges in the rat. 767

The role of mitogen-activated protein kinase (MAPK, also known as extracellular signal regulated kinase; ERK) stimulation in gonadotropin-releasing hormone (GnRH) signaling was investigated in cultured pituitary cells of tilapia hybrids (Oreochromis niloticus x O. aureus). Exposure of the cells to salmon GnRH (sGnRH) resulted in a dose- and time-dependent elevation in ERK levels. The PKC activator, 1-O-tetradecanoyl phorbol-13-acetate (TPA) increased kinase levels, while addition of GnRH had no further effect. However, chronic exposure to TPA resulted in reduction of basal and GnRH-induced ERK elevation. When PKC was inhibited by GF109203X, the GnRH-elevated ERK levels were totally abolished. The role of MAPK activation on GPalpha, FSHbeta and LHbeta gene expression was determined by administration of MAPK-kinase (MEK) inhibitor (PD98059; PD). This inhibitor completely blocked GnRH-induced increases in ERK activity. Furthermore, it suppressed GPalpha and LHbeta mRNA responses to GnRH, but had no effect on FSHbeta transcript levels. PD also decreased basal LHbeta mRNA levels. These results indicate that in tilapia pituitary cells, GnRH activates MAPK cascade in a PKC-dependent manner. ERK is involved in GnRH elevation of GPalpha and LHbeta, but not in FSHbeta genes transcription.
 ...
PMID:GnRH receptor signaling in tilapia pituitary cells: role of mitogen-activated protein kinase (MAPK). 1139 87

The hypothalamic gonadotropin-releasing hormone (GnRH) is a key regulator of the reproductive system, triggering the synthesis and release of LH and FSH in the pituitary. GnRH transmits its signal via two specific serpentine receptors that belong to the large group of G-protein coupled receptors (GPCRs). Here we review the intracellular signaling pathways mediated by the GnRH receptor (GnRHR). In pituitary-derived alpha T3-1 cells, a widely used model for GnRH action, GnRHR signaling includes activation of mitogen-activated protein kinase (MAPK) cascades, which provide an important link for the transmission of signals from the cell surface to the nucleus and play a role in the regulation of gonadotropin transcription. Activation of ERK--one of the MAPK cascades--by GnRH in these cells depends mainly on the phosphorylation of Raf1 by PKC, supported by a pathway involving c-Src, dynamin, and Ras. On the other hand, the activation of JNK, another MAPK cascade, involves PKC, c-Src, CDC42/Rac1, and probably MEKK1. The GnRHR is also expressed in non-pituitary cells and was found to be involved in the inhibition of cell proliferation in certain cells. Therefore, GnRHR represents a potential target for GnRH-analogs used for cancer treatment. Interestingly, the signaling mechanism of the GnRHR in other cell types significantly differs from that in pituitary cells. Studies conducted in GnRHR-expressing COS7 cells have shown that GnRHR transmits its signals mainly via Gi, EGF receptor, c-Src, and is not dependent on PKC. Understanding the signaling mechanisms elicited by GnRHR can shed light on the mechanism of action of GnRH in pituitary and extra-pituitary tissues.
 ...
PMID:Intracellular signaling pathways mediated by the gonadotropin-releasing hormone (GnRH) receptor. 1175 Jul 25

In the female rabbit, coitus induces a massive release of hypothalamic gonadotropin-releasing hormone (GnRH) within 20 min. The GnRH surge is preceded by an increase in hypothalamic norepinephrine (NE) release. Presumably, coitus stimulates NE, hence GnRH, release by increasing the activity of tyrosine hydroxylase (TH, the rate-limiting enzyme for NE synthesis) and/or decreasing the activity of norepinephrine transporter (NET, the key protein for NE re-uptake). Since NE cell bodies are located primarily in the brainstem, we hypothesize that coital signals are relayed to hypothalamic GnRH-secreting neurons via brainstem NE-containing perikarya. In support of this hypothesis, we found that both c-fos and TH mRNA expressions in brainstem noradrenergic areas, particularly in the A1 and A2 cell groups, increased within 30 min and returned to precoital levels within 60 min after coitus. Here we analyzed coitally induced changes in NET mRNA expression at 0, 15, 30 and 60 min postcoitus in the brainstem by in situ hybridization, using 35S-labeled rabbit NET RNA probes. In comparison with nonmated females (i.e., at 0 min), the expression of NET mRNA significantly increased (P<0.05) within 15 min postcoitus in the A1, but not the A2 area. By 30 min postcoitus, NET gene expression increased in the caudal portion of the A1 and in the caudal and central portion of the A2. By 60 min postcoitus, NET mRNA expression in the caudal and rostral portion of the A1 and the caudal and central portion of the A2 was still higher than NET mRNA expression in nonmated rabbits (P<0.05). No change in NET mRNA expression was observed in the A6. The results suggest that coitus increases NET mRNA expression in A1 and A2 noradrenergic areas within 15-30 min, and this enhanced NET mRNA expression was maintained for at least 60 min, particularly in the A2. These findings, in combination with our previous observation on increased TH gene expression within 30 min, but not 60 min, after coitus, further suggest that the coitus-induced NET transcriptional events within brainstem NE neurons may play an important role in the maintenance, and particularly in the termination, of hypothalamic NE release, hence regulating the size and duration of the coitus-induced GnRH surge.
 ...
PMID:Norepinephrine transporter mRNA expression after coitus in the rabbit brainstem. 1176 82

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.
 ...
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


1 2 3 4 5 6 7 8 9 10 Next >>