Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fetal muscle-like acetylcholine receptors (AChRs) are composed of alpha, beta, gamma, delta subunits (gamma-AChRs) and have a rapid half life (t1/2), whereas adult muscle-like AChRs are composed of alpha, beta, epsilon, delta subunits (epsilon-AChRs) and have a slow t1/2. Two populations of AChRs, a slowly degrading population and a rapidly degrading population, have been shown to coexist in the postsynaptic membrane after denervation [In: Penn et al. (Eds.), Myasthenia Gravis and Related Disorders, Vol. 681, NY Acad. Sci., 1993, pp. 155-164]. Treatment of rat myotubes or mouse diaphragm muscle in organ culture with forskolin or cAMP analogues causes and increase in the t1/2 of the slowly degrading population of AChRs with no apparent effect on the rapidly degrading population of AChRs19. In this study, we have investigated the effect of forskolin on the cell surface half-lives of mouse gamma-AChRs, epsilon-AChRs and alpha beta delta complexes stably expressed in mouse fibroblasts. Forskolin had no significant effect on the t1/2 of gamma-AChRs or alpha beta delta complexes. The effect of forskolin on surface AChRs (alpha beta gamma delta) expressed in the C2 muscle cell line was similar to its effect on gamma-AChRs expressed in fibroblasts. In contrast, forskolin stabilized the epsilon-AChRs by approximately 2 fold. We show that the epsilon-subunit is phosphorylated in vivo, phosphorylation of epsilon increases with forskolin treatment, and the forskolin effect is reversible. Although the precise role of epsilon-subunit phosphorylation is yet to be determined, our results support the hypothesis that the slowly degrading population of AChRs consists of epsilon-AChRs and the rapidly degrading population of AChRs consists of gamma-AChRs.
Brain Res Mol Brain Res 1994 Oct
PMID:Forskolin stabilizes epsilon subunit-containing acetylcholine receptors. 785 59

L-type calcium currents were studied in ventricular myocytes isolated from non-failing hearts, i.e. donor hearts not suitable for transplantation, and from severely failing hearts, i.e. explanted hearts of organ recipients, in order to identify possible alterations of the currents in cardiomyopathy. Human atrial myocytes were investigated for comparative purposes. As deficient production of cyclic AMP might contribute to the development of cardiac failure, the responses to forskolin, a direct stimulator of adenylyl cyclase, were also studied. The patch-clamp technique was applied in the single electrode whole-cell mode. Calcium currents were similar in myocytes from non-failing and failing hearts: Maximum current-densities were 3.8 v 3.1 pA/pF, and 2.2 pA/pF in atrial cells. In human ventricular cells, threshold was at -33 mV, maximum at +6 mV and reversal potential at about +50 mV, potentials of half-maximum steady-state inactivation -24 mV and -18 mV. The slopes of steady-state inactivation curves were +4.1 mV in myopathic and +5.5 mV in non-failing cells. In all myocytes the current inactivated with two time constants, a fast one with weak and a slow one with pronounced potential dependency. Ventricular or atrial myocytes from patients pretreated with calcium antagonists and untreated did not differ in current density or steady-state inactivation. Forskolin (0.5 microM) increased calcium currents in myocytes from non-failing and failing hearts to the same extent (by 143 and 150%). While beta-adrenoceptor numbers are reported to decline in severely failing myocardium, our data do not suggest that alterations of the properties of calcium currents contribute to the pathophysiology of heart failure, though the number of investigated hearts is limited due to restricted access to non-failing cardiac tissue. No evidence for impairment of the signal transduction cascade beyond the level of GTP binding proteins was found.
J Mol Cell Cardiol 1994 Oct
PMID:L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. 786 91

This report describes chloride and iodide effluxes across the basolateral membrane of porcine thyroid follicles reconstituted in culture. Basolateral chloride efflux is activated by thyrotropin (TSH). TSH (10 mU/ml) induces a twofold increase in the initial rate of chloride efflux. Forskolin (FSK, 5 microM) which increases intracellular cAMP also stimulates the initial rate of chloride efflux 3.5-fold, whereas an increase in the free cytosolic Ca2+ with the ionophore A23187 or thapsigargin, fails to mimic the TSH effect. The chloride channel blocker 5-nitro-2(3-phenylpropylamino)benzoic acid (NPPB) dose dependently inhibits chloride efflux rates with the maximal and half maximal effects observed for 100 microM and 30 microM, respectively. Basolateral chloride efflux rates are also inhibited in the presence of the organic anion transporter blocker probenecid (5 mM) or the Cl-/HCO3- exchanger blocker 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS, 250 microM), respectively, by 60% and 40%, whereas it is not affected by ClO4 (100 microM). The initial rate of iodide efflux is weakly activated (1.4-fold) by TSH (10 mU/ml). TSH effect could be reproduced by agents known to activate Ca(2+)-dependent processes as A23187, ionomycin (1 microM), phorbol 12-myristate 13-acetate (TPA, 0.1 microM) and epidermal growth factor (EGF, 0.1 microM) which increase the initial rate of iodide efflux from 1.2- to 1.8-fold, whereas FSK is without effect. The chloride channel blocker NPPB (500 microM) is required to significantly inhibit the initial rate of iodide efflux by 30%. The initial rate of iodide efflux is also reduced by 30% in the presence of SITS (250 microM) or probenecid (5 mM) whereas it is activated by ClO4 (100 microM). We conclude that basolateral chloride and iodide effluxes are both regulated by TSH, using two different transduction pathways. Chloride efflux regulation may involve a cAMP transduction signal, whereas the regulation of iodide efflux may involve a Ca2+ signal. Furthermore, as the sensitivities of chloride and iodide effluxes for the anion transporter blockers (especially NPPB) are different, it seems likely that chloride and iodide use two different transport pathways.
Mol Cell Endocrinol 1994 Dec
PMID:Thyrotropin regulation of basolateral Cl- and I- effluxes in thyroid follicles in culture. 789 8

The 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS) genes are a set of primary response genes induced in Swiss 3T3 cells by TPA. They include three transcription factors, a prostaglandin synthase, and three proteins of unknown function. To ascertain which, if any TIS genes might be involved in tumor promotion, we examined the expression of these genes in response to tumor promoters in transformation promotion-sensitive (P+) and -resistant (P-) JB6 murine epidermal cells, a model used to identify events relevant to promotion. A subset of TIS genes (TIS1, TIS10, and TIS21) was preferentially induced by TPA in P-cells. In addition, TIS1 and TIS21 mRNAs were preferentially induced in P-cells by epidermal growth factor, another transformation promoter that distinguishes P+ from P-cells. TIS1 and TIS21 protein levels were also greater in TPA-treated P-cells than P+ cells. Forskolin, a cAMP-elevating anti-promoter, increased TPA-induced levels of TIS1, TIS10, and TIS21 mRNAs in P+ cells, ruling in potential roles for these genes in modulating tumor promotion. The anti-promoters fluocinolone acetonide, retinoic acid, and superoxide dismutase did not enhance TPA-induced levels of TIS1 and TIS21 mRNAs in P+ cells, suggesting that these inhibitors may act on other promotion-relevant genes. TIS1 encodes a member of the steroid receptor superfamily. TIS1 encodes a protein of unknown function with strong sequence similarity to BTG1, a proposed "anti-proliferative gene" (Rouault JP, Rimokh R, Tessa C, et al., EMBO J 11:1663-1670, 1992). Preferential induction by multiple promoters of these TIS genes in P-cells and enhancement of their induction in P+ cells by the anti-promoter forskolin make TIS1 and TIS21 candidates for promotion suppressor genes.
Mol Carcinog 1994 Oct
PMID:Preferential primary-response gene expression in promotion-resistant versus promotion-sensitive JB6 cells. 791 93

When PC-12 cells were treated with 10 microM forskolin, the expression of two members of the granin family, secretogranin II (SgII) and chromogranin B (CgB), were differentially regulated. SgII mRNA levels declined progressively after forskolin treatment to reach a level of 22 +/- 1% of control after 48 hr, whereas CgB mRNA levels increased more rapidly, reaching a maximum of 3-fold above control after 24 hr. The dependence of these changes on an increase in cellular cAMP levels, activation of cAMP-dependent protein kinase (PKA), protein synthesis, and changes in the rate of transcription was investigated. The effects of forskolin on SgII and CgB mRNAs were reproduced by 1 mM 8-bromo-cAMP but not by 10 microM 1,9-dideoxyforskolin, an inactive analog of forskolin. The actions of forskolin on SgII and CgB mRNAs were blocked by treatment with 60 microM H-89, a selective PKA inhibitor, and were blunted in PKA-deficient PC-12 cell clones. To examine whether forskolin action was dependent on ongoing protein synthesis, PC-12 cells were treated with 1 microgram/ml cycloheximide before the addition of forskolin. The reduction in SgII mRNA levels by forskolin was not evident in PC-12 cells treated with cycloheximide. Rather, in the presence of cycloheximide, forskolin stimulated SgII mRNA levels 3.6 +/- 0.7-fold above control. The induction of CgB mRNA by forskolin was not affected by cycloheximide treatment. The superinduction of SgII mRNA by cycloheximide and forskolin was related to the extent of protein synthesis inhibition, was observed in cells treated with forskolin and other protein synthesis inhibitors, and was blunted in PKA-deficient PC-12 cells, suggesting that this effect was dependent on inhibition of protein synthesis and activation of PKA. To determine whether changes in SgII and CgB mRNA levels resulted from changes in the rate of transcription, nuclear run-on assays were performed in nuclei isolated from PC-12 cells that had been treated for 2 hr with cycloheximide, forskolin, or the two combined. Transcription of the SgII gene was not significantly affected by treatment with either forskolin or cycloheximide alone but was increased 12.9 +/- 1.0-fold above control in nuclei from cells treated with cycloheximide and forskolin together. Forskolin caused a 3.8 +/- 0.8-fold induction of CgB transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1994 Nov
PMID:Transcriptional regulation of secretogranin II and chromogranin B by cyclic AMP in a rat pheochromocytoma cell line. 796 75

The role of the cumulus cells in initiating the resumption of meiosis after exposure to forskolin and dbcAMP was studied in the mouse. The resumption of meiosis was monitored by the percentage of germinal vesicle breakdown (GVBD) and polar body formation (PB). The cumulus-enclosed oocytes (CEO) and denuded oocytes (DO) were cultured with and without hypoxanthine (HX) in the culture medium. Three types of experiments were performed: (1) Effect of forskolin on spontaneous resumption of meiosis, i.e. cultures without HX, and two experiments in which HX is present throughout the culture: (2) Effect of transient exposure to forskolin or dibutyric-cyclic adenosinemonophosphate (dbcAMP) on GVBD prior to continued culture without forskolin or dbcAMP (oocyte priming). (3) Priming of CEO with forskolin for 2 hr, separation of cumulus cells and oocytes, followed by coculture of rejoined cumulus cells and oocytes, or coculture of the cumulus cells and new, unprimed DO. (1) Forskolin inhibited a spontaneous resumption of meiosis in a dose-dependent manner during the first 5 hr of culturing. After 22 hr all controls and CEO resumed meiosis, whereas only half of the DO did. (2) At least 1 hr of priming the CEO with forskolin is needed to induce GVBD and PB formation, but forskolin inhibited the resumption of meiosis when present for 24 hr. Similar results were obtained with a high concentration of dbcAMP. (3) A separation and rejoining of oocytes and cumulus cells after priming induced the resumption of meiosis in a significantly greater number of oocytes than in the control oocytes which were not primed.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1994 Sep
PMID:Cumulus cells secrete a meiosis-inducing substance by stimulation with forskolin and dibutyric cyclic adenosine monophosphate. 799 57

Intracellular pathways mediating feedback regulation by insulin-like growth factor-1 (IGF-1) of pituitary GH gene expression remain incompletely understood. Extracellular signal-related kinases (ERKs), a family of serine/threonine kinases, are activated by tyrosine kinase-associated growth factor receptors. To further define the IGF-1 postreceptor events occurring in GH-secreting cells, we investigated the activity of ERKs in response to IGF-1 in GC cells following stable transfection with either wild type human IGF-1 receptor cDNA (WT cells) or a mutant cDNA encoding a truncated, kinase-defective IGF-1 receptor with a dominant negative effect on endogenous receptor function (952STOP cells). Zymography of immunoprecipitated ERKs in myelin basic protein (MBP)-containing polyacrylamide gels demonstrated dose-dependent induction of ERK-1 and -2 activity by IGF-1 in GC cells with maximal activity occurring at 6 min. IGF-1-induced ERK activity in WT-transfected cells was up to 80-fold basal and 4-fold that observed in GC cells. 952STOP cells expressing the tyrosine kinase-deficient receptor were refractory to IGF-1 action, demonstrating minimal ERK induction. In contrast, 12-O-tetradecanoylphorbol 13-acetate stimulated ERK activity to the same degree in all three cell types regardless of their IGF-I receptor status. Forskolin (50 microM), isobutylmethylxanthine (0.5 mM), and forskolin/isobutylmethylxanthine in combination attenuated IGF-1-induced ERK activity in WT cells by 54, 55, and 75% respectively. The rapid, dose-dependent, and IGF-1 receptor-dependent activation of ERKs and the attenuation of this effect by cAMP suggest an interrelated role for both molecules in IGF-1 signal transduction in GH-secreting cells.
Mol Endocrinol 1994 May
PMID:Insulin-like growth factor-1 activation of extracellular signal-related kinase-1 and -2 in growth hormone-secreting cells. 805 64

Sodium nitroprusside spontaneously breaks down in solution to produce the vasodilator nitric oxide. In many cell types, this stimulates the cytosolic form of the enzyme guanylate cyclase, resulting in the elevation of cyclic GMP (cGMP). We have investigated the effect of sodium nitroprusside on the generation of cGMP in primary human thyrocytes and the SV40-transfected human thyroid cell line SGHTL-189. A dose-dependent increase in cGMP was obtained and the maximum response was observed with concentrations above 10 microM sodium nitroprusside in both cell types. Methylene blue (50 microM) had no significant effect on basal cGMP production but inhibited the effect of sodium nitroprusside at all concentrations tested, thus demonstrating that the effect was due to nitric oxide. Sodium nitroprusside had no effect on cyclic AMP (cAMP) production in these cells. TSH at 100 and 1000 microU/ml significantly stimulated the production of cAMP, but not that of cGMP, in primary human thyrocytes. Sodium nitroprusside had no significant effect on basal or TSH-stimulated triiodothyronine secretion in primary human thyrocytes. Forskolin (10 microM) significantly stimulated cAMP production in both primary thyrocytes and SGHTL-189 cells. Although forskolin had no significant effect on basal cGMP production, sodium nitroprusside-stimulated cGMP production was significantly reduced by forskolin. However, this inhibitory effect was not related to the production of cAMP.
J Mol Endocrinol 1993 Apr
PMID:Nitric oxide stimulates cyclic GMP in human thyrocytes. 809 15

Intracellular effector systems which utilize PKA and PKC can be pharmacologically activated by forskolin and phorbol 12-myristate 13-acetate (PMA) and appear to be important for regulation of steroidogenesis by cells of the corpus luteum. In this study the effect of pharmacologic activation of PKA (forskolin) or PKC (PMA) on the activity of adenylate cyclase, cholesterol esterase, P450 cholesterol side chain cleavage (P450scc) and 3 beta-hydroxysteroid dehydrogenase/delta 5, delta 4 isomerase (3 beta HSD) was determined. Basal adenylate cyclase activity (as measured by intracellular and secreted cAMP) was extremely low in both large and small luteal cells. Forskolin stimulated adenylate cyclase activity in both large and small luteal cells but progesterone production was increased only in small cells. PMA inhibited progesterone production by large and forskolin-stimulated small cells without altering adenylate cyclase activity. Basal cholesterol esterase activity was greater in small than in large cells and was stimulated by forskolin only in small cells. PMA did not significantly alter cholesterol esterase activity in either cell type. Activity of P450scc or 3 beta HSD was measured by conversion of hydroxylated cholesterol derivatives (P450scc) or pregnenolone (3 beta HSD) to progesterone. Although basal progesterone production was 47 times greater in large than small cells, there was only 5.1 (P450scc) and 6.4 (3 beta HSD) times greater enzyme activity in large than in small luteal cells. Activation of PKA and/or PKC did not alter the activity of P450scc or 3 beta HSD in either cell type.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1993 Nov
PMID:Steroidogenic enzyme activity after acute activation of protein kinase (PK) A and PKC in ovine small and large luteal cells. 814 91

Corticotropin (ACTH) binds to specific receptors in the adrenal cortex and thereby regulates glucocorticoid and mineralocorticoid production. The number of ACTH binding sites on adrenocortical cells is increased by exposure of cells to activators of the cAMP pathway. The mechanism responsible for the increase in ACTH binding sites is not known. We therefore studied the levels of ACTH-R mRNA in mouse Y-1 and human NCI-H295 (H295) adrenocortical carcinoma cell lines. ACTH induced an increase in mouse ACTH-R mRNA in Y-1 cells that was time and dose dependent, increasing 6-fold over basal levels following exposure to 10(-8) M ACTH for 19-24 h. The amount of human ACTH-R mRNA in H295 cells increased 2-4-fold following a 24 h exposure to 10(-8) M ACTH, 1 mM dbcAMP, or 10(-5) M Forskolin. Treatment of H295 cells with angiotensin II (A-II) was found to dramatically increase the level of ACTH-R mRNA. These data indicate that regulation of ACTH-R mRNA levels is at least one mechanism by which ACTH and A-II elevate the number of ACTH binding sites in the adrenocortical cells.
Mol Cell Endocrinol 1994 Feb
PMID:ACTH induces up-regulation of ACTH receptor mRNA in mouse and human adrenocortical cell lines. 818 50


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