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)

Adenylate cyclase in plasma membranes was inhibited by micromolar concentrations of delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol and by levonantradol and desacetyllevonantradol. This inhibition was noncompetitive for stimulation of the enzyme at the prostanoid receptor by prostaglandin E1 or prostacyclin, or at the peptide receptor by secretin or vasoactive intestinal peptide. Forskolin-activated adenylate cyclase was also inhibited by cannabimimetic agents. Inhibition by cannabinoid compounds was neither synergistic nor additive with muscarinic or alpha-adrenergic agents when each was present at maximally inhibitory concentrations. Cannabinoid inhibition was not blocked by atropine, yohimbine, or naloxone, suggesting that muscarinic, alpha 2-adrenergic and certain opiate receptors may not be required for the response. The inhibition of adenylate cyclase was specific for psychoactive cannabinoids, since cannabinol and cannabidiol produced minimal or no response. Inhibition was also stereoselective, since dextronantradol did not produce the response. A biphasic log dose-response curve was observed for each of the cannabinoid drugs, such that reversal of the inhibition occurred at 3-10 microM. Possible mechanisms for the effects of cannabinoid drugs on adenylate cyclase activity are discussed.
Mol Pharmacol 1984 Nov
PMID:Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. 609 1

The effects of an LHRH agonist on LH- and forskolin-stimulated cyclic AMP and testosterone production have been investigated in purified rat Leydig cells in vitro. In agreement with previous results it was found that preincubation with LHRH agonist inhibited subsequent LH-stimulated cyclic AMP production. At least 2 h preincubation was required and this effect of the LHRH agonist was negated by the protein synthesis inhibitor cycloheximide and by the phosphodiesterase inhibitor methylisobutylxanthine (MIX). Forskolin-stimulated cyclic AMP production was not inhibited by the LHRH agonist. Forskolin increased testosterone production to the same levels attained by LH and preincubation with LHRH agonist increased both forskolin- and LH-stimulated testosterone production. The data obtained suggest that LHRH agonist increases the synthesis of an inactive form of phosphodiesterase (or associated protein) which is activated by LH via a mechanism not involving cyclic AMP.
Mol Cell Endocrinol 1984 Jun
PMID:LHRH agonist decreases LH- but not forskolin-stimulated cyclic AMP levels in rat Leydig cells in vitro. 620 93

The effect of forskolin (an adenyl cyclase activator) and 1-methyl-3-isobutylxanthine (MIX, a phosphodiesterase inhibitor) on granulosa cell steroidogenesis and LH receptor formation was studied in vitro. Granulosa cells from immature hypophysectomized, estrogen-treated rats were cultured for 2-3 days in androstenedione-supplemented media in the absence or presence of FSH or forskolin (10(-7)-10(-4) M). Some cultures were also treated with forskolin with or without MIX (0.125-1.0 mM) or theophylline (1.25-10 mM). Forskolin (3 X 10(-6)-10(-4) M) stimulated the production of estrogen, progesterone, 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OH-P) and cAMP in a dose-related manner to levels similar to or higher than that elicited by FSH alone. Similarly, forskolin and FSH both increased LH/hCG receptor content in cultured granulosa cells, although forskolin was only 50% as effective as FSH. Treatment with MIX alone increased basal levels of cAMP, accompanied by elevations of estrogen and progestin biosynthesis without affecting LH/hCG receptor content. In contrast, theophylline treatment only increased cAMP and progestin accumulation. Furthermore, MIX potentiated the stimulatory effects of forskolin and FSH on cAMP and progestin production. In contrast, MIX inhibited FSH- and forskolin-stimulated estrogen production. Thus, activation of adenyl cyclase and inhibition of cAMP breakdown in the cultured rat granulosa cells enhance steroidogenesis and LH receptor formation, reinforcing the concept that cAMP is a (but may not be the only) second messenger in the hormonal regulation of granulosa cell differentiation.
Mol Cell Endocrinol 1984 Aug
PMID:Forskolin and phosphodiesterase inhibitors stimulate rat granulosa cell differentiation. 620 17

Forskolin increased cyclic AMP accumulation in isolated adipocytes and markedly potentiated the elevation of cyclic AMP due to isoproterenol. In adipocyte membranes, forskolin stimulated adenylate cyclase activity at concentrations of 0.1 microM or greater. Forskolin did not affect the EC50 for activation of adenylate cyclase but did increase the maximal effect of isoproterenol. Neither the soluble nor particulate low-Km cyclic AMP phosphodiesterase activity was affected by forskolin. Low concentrations of forskolin (0.1-1.0 microM), which significantly elevated cyclic AMP levels, did not increase lipolysis, whereas similar increases in cyclic AMP levels due to isoproterenol elevated lipolysis. Forskolin did not inhibit the activation of triacylglycerol lipase by cyclic AMP-dependent protein kinase or the subsequent hydrolysis of triacylglycerol. Higher concentrations of forskolin (10-100 microM) did increase lipolysis. Both the increased cyclic AMP production and lipolysis due to forskolin were inhibited by the antilipolytic agents insulin and N6-(phenylisopropyl)adenosine. Hypothyroidism reduced the ability of forskolin to stimulate cyclic AMP production and lipolysis. These results indicate that forskolin increases cyclic AMP production in adipocytes through an activation of adenylate cyclase. Lipolysis is activated by forskolin but at higher concentrations of total cyclic AMP than for catecholamines.
Mol Pharmacol 1982 Jul
PMID:Forskolin as an activator of cyclic AMP accumulation and lipolysis in rat adipocytes. 628 66

The ability of the diterpene forskolin to stimulate cyclic AMP accumulation in intact cell and membrane preparations of wild-type S49 lymphoma cells (WT) and a number of variants has been confirmed. Additionally, a number of salient new findings have emerged: (a) A time delay in forskolin stimulation of cyclic AMP accumulation and adenylate cyclase (t 1/2 approximately equal to 1.5 min) occurred in all hormone-sensitive WT and variant cell and membrane preparations tested. (b) The time delay was missing in the adenylate cyclase-deficient variant (cyc-) of the S49 lymphoma cell, which also lacks functional adenylate cyclase-coupling proteins. (c) The simultaneous addition of epinephrine and forskolin to WT cells or to membrane preparations eliminated the time delay. (d) Forskolin stimulation of intact WT cells did not appear to desensitize adenylate cyclase. (e) The activation of WT adenylate cyclase by forskolin was biphasic with respect to concentration, with both high- and low-affinity components being apparent. In cyc-, only the low-affinity component was detected.
Mol Pharmacol 1982 Nov
PMID:Differences in the forskolin activation of adenylate cyclases in wild-type and variant lymphoma cells. 629 54

Forskolin, a diterpene hypotensive drug, activates adenylate cyclase in brain and in some other tissues (Seamon et al., 1981). Forskolin activated adenylate cyclase in particulate preparations and enhanced cyclic AMP accumulation in slices of dog thyroid. These effects were maximal within minutes and remained constant afterwards. The action of forskolin on intact cells disappeared rapidly after washing. It reproduced two known cyclic AMP-mediated TSH effects: the activation of secretion and of protein iodination. Forskolin thus provides a very convenient tool for the study of the action of defined elevations of cyclic AMP level in thyroid cells. The activation by forskolin of adenylate cyclase was not reduced by Mn2+ which uncouples TSH and PGE1 action. This suggests that in the thyroid also, forskolin acts beyond the receptor level. The effect of forskolin on cyclic AMP accumulation was inhibited by the known negative regulators of this system in the thyroid, acetylcholine, iodide, norepinephrine, PGF1 alpha and adenosine. On the other hand, forskolin potentiated the effects of TSH, PGE1 and cholera toxin. These data show that, though it does not require the receptors for its action, forskolin does not uncouple them from the catalytic unit of adenylate cyclase.
Mol Cell Endocrinol 1983 Jan
PMID:Stimulation by forskolin of the thyroid adenylate cyclase, cyclic AMP accumulation and iodine metabolism. 629 30

The responsiveness of anterior pituitary tumor (GH3) cells to promoters of prolactin secretion and/or synthesis and cyclic AMP accumulation was studied as a function of cellular Ca2+ content. GH3 cells exposed to media containing 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid were reduced 7-fold in Ca2+ content without loss of viability. Preparations of Ca2+-depleted cells were largely unchanged in cyclic AMP content when challenged by thyrotropin-releasing hormone (TRH), whereas cells which were subsequently restored at optimal Ca2+ (0.5 mM) responded to the hormone with 2- to 3-fold increases in cyclic AMP content. The decreased responsiveness of Ca2+-depleted cells to TRH was not influenced by phosphodiesterase inhibitors, incubation time, or hormone concentration. TRH-dependent cyclic AMP accumulation was markedly potentiated by forskolin in Ca2+-restored, but not in Ca2+-depleted, cell preparations. Forskolin extended the time period during which cyclic AMP accumulated in response to TRH without altering the TRH concentration dependency of the cells. Varying increases in GH3 cyclic AMP content occurred in response to other hormones or agents which enhance prolactin secretion and/or synthesis. In Ca2+-restored cells, cyclic AMP content was increased 2-fold by prostaglandin E1 (PGE1) and epidermal growth factor (EGF), 10- to 15-fold by vasoactive intestinal polypeptide (VIP) and 6-fold by phorbol myristate acetate (PMA); the capacity of Ca2+-depleted cells, however, to accumulate cyclic AMP in response to PGE1, EGF, and VIP was greatly reduced. Accumulation of cyclic AMP following short-term incubations with cholera toxin similarly was dependent on Ca2+. Exposure of GH3 cells preloaded with 45Ca to TRH, PGE1, EGF, PMA, or VIP resulted in losses of cell-associated 45Ca. Pretreatment with these agents resulted in a decreased capacity of the cells to accumulate 45Ca from the extracellular medium. The results of this study support the hypothesis that various putative humoral regulators of prolactin secretion and/or synthesis act on GH3 cells to alter intracellular Ca2+ metabolism which in turn results in an increased cyclic AMP content through stimulation of adenylate cyclase activity.
Mol Pharmacol 1983 Mar
PMID:Regulation of Ca2+-dependent cyclic AMP accumulation and Ca2+ metabolism in intact pituitary tumor cells by modulators of prolactin production. 630 Jun 49

The diterpene forskolin was found to activate the adenylate cyclase system in intact tissue and membrane preparations of the immature rat ovary. The cyclic AMP (cAMP) response reached a maximal level after 5 min and no decline was observed even after 4 h of incubation. Forskolin stimulated production of both progesterone and testosterone in a pattern similar to that produced by luteinizing hormone (LH) or dibutyryl-cAMP (dbcAMP). In combination with LH, follicle-stimulating hormone (FSH) or prostaglandin E2 (PGE2), forskolin potentiated the hormone effects on adenylate cyclase activity in membrane preparations. Pretreatment with LH or PGE2 desensitized the cells to further hormone stimulation, while the forskolin response was unaffected. Pre-exposure to forskolin did not desensitize the cells to a subsequent stimulation by LH or PGE2. The presence of 8-bromo-cAMP (brcAMP) in the preincubation medium reduced the subsequent hormone response. These results demonstrate a rapid and sustained activation of the adenylate cyclase system by forskolin in the rat ovary. The steroidogenic response was similar to that of known stimulators of ovarian cells (LH, dbcAMP). The inability of forskolin to induce desensitization of the adenylate cyclase system demonstrates, however, important differences between hormone and non-hormone activation. Consequently, forskolin can be a useful tool for investigation of the mechanisms involved in the desensitization process.
Mol Cell Endocrinol 1983 Nov
PMID:Forskolin effects on the cAMP system and steroidogenesis in the immature rat ovary. 631 10

Forskolin activates a variety of adenylate cyclase systems and acts synergistically with receptor-mediated agonists which stimulate cyclic AMP production. The mechanism(s) and site(s) of forskolin action remain unclear. In C6-2B rat astrocytoma cells, forskolin stimulated greater than a 100-fold increase in cellular cyclic AMP content with a half-maximally effective concentration (EC50) of greater than 50 microM. Incubation of C6-2B cells with forskolin plus (-)-isoproterenol resulted in an increase in (-)-isoproterenol efficacy and potency. The EC50 for the forskolin-induced increase in (-)-isoproterenol potency was 22 nM, greater than 3 orders of magnitude lower than the EC50 for direct forskolin-stimulated cyclic AMP accumulation. Forskolin had no effect on beta-receptor affinity for (-)-isoproterenol as measured by competition for (-)-[125I]iodopindolol binding sites. Forskolin also augmented the responses to prostaglandin E1 and cholera toxin. Inhibition of protein synthesis with cycloheximide markedly reduced forskolin-stimulated cyclic AMP accumulation with little or no effect on the responses to (-)-isoproterenol, prostaglandin E1, or cholera toxin. The ability of forskolin to act synergistically with these agents was unaffected by cycloheximide treatment. These observations are compatible with a two-site model of forskolin action in C6-2B cells: a low-affinity site which mediates the direct action of forskolin to increase cellular cyclic AMP accumulation and a high-affinity site which mediates the potentiative action of forskolin. The low-affinity forskolin site appears to reside on a protein which is closely associated with the catalytic adenylate cyclase moiety and has a relatively shorter half-life than other components of the cyclase system. The high-affinity site resides on a more stable component of the adenylate cyclase system. The synergistic action of forskolin may involve an enhancement of the interaction between the guanine nucleotide-binding regulatory component and the catalytic component of the adenylate cyclase complex.
Mol Pharmacol 1984 Mar
PMID:Distinct mechanisms of forskolin-stimulated cyclic AMP accumulation and forskolin-potentiated hormone responses in C6-2B cells. 632 48

Forskolin, a potent activator of adenylate cyclase, has been proposed to activate this enzyme by a direct interaction with the catalytic subunit. To test this hypothesis, we examined the effects of forskolin on sperm cyclic AMP content and sperm adenylate cyclase activity. Forskolin or cholera toxin did not increase cyclic AMP content in either bull or boar sperm, whereas the inhibitors of phosphodiesterase, caffeine and methylisobutylxanthine, significantly increased sperm cyclic AMP content. Forskolin, NaF, and guanylimidodiphosphate did not activate the adenylate cyclase of either sperm membranes or cytosol. When homogenates of rat, guinea pig, or bull testes were centrifuged at 100,000 X g, the supernatant was found to contain a forskolin-stimulated adenylate cyclase. Further centrifugation of this 100,000 X g supernatant fraction at 250,000 X g for 3 hr quantitatively sedimented the forskolin-sensitive enzyme activity. We conclude that forskolin does not activate either the cytosolic or membrane-bound adenylate cyclase of mammalian sperm.
Mol Pharmacol 1983 Jul
PMID:Forskolin does not activate sperm adenylate cyclase. 668 55


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