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)

This report demonstrates that the D-2 dopamine receptors that are present in rat striatum can directly inhibit the activity of adenylate cyclase in a GTP-dependent manner. N-n-propylnorapomorphine evoked a more pronounced inhibition than did dopamine. However, in the presence of the D-1-selective antagonist, SCH 23390, dopamine was also observed to inhibit the enzyme. Forskolin facilitated the detection of D-2 receptor-mediated inhibition by markedly stimulating striatal adenylate cyclase activity. The inhibition was antagonized in a dose-dependent manner by the D-2 receptor antagonist spiperone (Ki value = 70 pM) and was absolutely dependent on the presence of both GTP and sodium ions. Inhibition produced via D-2 receptors was additive with that produced via opiate or adenosine A1 receptors. The nonhydrolyzable GTP analogue, 5'-guanylylimidodiphosphate [Gpp(NH)p], did not substitute for GTP in promoting the D-2 receptor-mediated inhibition. It thus appears that D-2 receptors mediate adenylate cyclase inhibition by processes that have been observed for other neurotransmitters in the striatum and elsewhere. In addition, Gpp(NH)p displayed a Ca2+/calmodulin dependency for its inhibitory effects that was not shared by receptor-mediated, GTP-dependent inhibition.
Mol Pharmacol 1986 Feb
PMID:Dopamine, acting through D-2 receptors, inhibits rat striatal adenylate cyclase by a GTP-dependent process. 300 24

The 7315c prolactin-secreting tumor cell was used as a model of a normal pituitary cell in order to study the enhancement by adenosine 3',5'-cyclic monophosphate (cAMP) of calcium-evoked hormone release. Forskolin and, by implication, cAMP had little effect on basal hormone release during a 10-min incubation period. Ionomycin and a high potassium concentration, treatments which enhanced the cytosolic calcium concentration, increased hormone release. When cells were exposed to forskolin prior to and during a challenge with either ionomycin or high potassium, a synergistic effect on prolactin release was observed. 8-Bromoadenosine 3',5'-cyclic monophosphate mimicked forskolin in enhancing ionomycin-evoked prolactin release while having little effect of its own on hormone release. Forskolin did not alter the increase in cytosolic calcium concentration elicited by either ionomycin or high potassium, nor did it increase the potency of ionomycin in enhancing prolactin release. The calcium channel antagonist, D-600, did not alter ionomycin-induced release or its enhancement by forskolin; D-600 blocked potassium-induced prolactin release. Ionomycin had no effect on basal cAMP synthesis by tumor cells and inhibited slightly the forskolin-induced increase in nucleotide synthesis. The results suggest that cAMP acts, at a site distal to the entry of calcium into the cytosol, to enhance the amount of prolactin released in response to an increase in the cytosolic calcium concentration.
Mol Pharmacol 1986 May
PMID:Forskolin enhances calcium-evoked prolactin release from 7315c tumor cells without increasing the cytosolic calcium concentration. 301 75

The hormonal regulation of thyroglobulin synthesis has been studied using two independent clones of the OVNIS 6H cell line. Insulin, hydrocortisone and TSH were able to stimulate thyroglobulin synthesis, whereas transferrin, somatostatin and glycyl-histidyl-lysine were without effect. Insulin stimulated thyroglobulin synthesis without affecting cAMP production. Hydrocortisone, when combined with insulin was a stimulator too; this stimulation was not accompanied by an increase in cAMP. TSH alone was unable to stimulate either cAMP or thyroglobulin synthesis. The stimulatory effect of TSH on thyroglobulin synthesis took place only when combined with insulin or insulin plus hydrocortisone, and was mediated by cAMP. Consequently, insulin and hydrocortisone stimulated thyroglobulin synthesis by cAMP-independent mechanisms, whereas TSH acted via the cAMP system. Forskolin mimicked TSH effects on cAMP and thyroglobulin synthesis. Calf serum inhibited cAMP and thyroglobulin production. Optimal cAMP and thyroglobulin synthesis as well as TSH responsiveness were obtained in serum-free medium supplemented with 5 micrograms/ml insulin, 100 nM hydrocortisone and 1 mU/ml TSH.
Mol Cell Endocrinol 1987 Jul
PMID:cAMP dependent and independent regulation of thyroglobulin synthesis by two clones of the OVNIS 6H thyroid cell line. 304 Apr 95

GH-releasing factor (GRF) and somatostatin regulates the secretion and biosynthesis of GH as well as the proliferation of GH-producing cells. In order to further characterize the mitogenic effect of GRF, we studied the expression of the proto-oncogene c-fos in primary pituitary cells. Maximal induction of c-fos mRNA was observed 20-60 min after stimulation with 5 nM GRF, returning to basal levels after 2 h. Somatostatin-14 (5 nM) partially inhibited the GRF induced c-fos expression. Forskolin and phorbol 12, 13 dibutyrate induced c-fos gene in cultured primary pituitary cells with similar kinetics. Transcription of the fos gene was accompanied by biosynthesis of the fos protein. Indirect immunofluorescence using a fos specific antibody, showed exclusive nuclear localization of the fos protein. These data demonstrate that GRF and somatostatin, in addition to regulating GH secretion and somatotroph proliferation, can also regulate the expression of c-fos proto-oncogene in primary somatotrophs.
Mol Endocrinol 1987 Apr
PMID:Growth hormone-releasing factor induces c-fos expression in cultured primary pituitary cells. 313 82

Forskolin and four analogues of forskolin, 7-beta-[gamma-(N'-methylpiperazino)-butyryloxy]-7-desacet ylforskolin, 7-desacetylforskolin, 7-tosyl-7-desacetylforskolin, and 1,9-dideoxyforskolin, were tested for their ability to activate adenylate cyclase, inhibit glucose transport, and inhibit cytochalasin B binding in rat adipocyte membranes. Forskolin was the most potent analogue in activating adenylate cyclase with an EC50 of 2 microM, whereas 7-beta-[gamma-(N'-methylpiperazino)butyryloxy]-7-desacety lforskolin and 7-desacetylforskolin were less potent, with EC50 values of 3 microM and 20 microM, respectively. The 7-tosyl-7-desacetylforskolin and 1,9-dideoxyforskolin did not stimulate adenylate cyclase even at the highest concentrations tested (100 microM). In contrast, forskolin and all of the analogues were able to fully inhibit glucose transport in adipocyte plasma membranes. The order of potency for the inhibition was forskolin greater than 7-beta-[gamma-(N'-methylpiperazino)butyryloxy]-7-desacety lforskolin greater than 7-desacetylforskolin greater than 7-tosyl-7-desacetylforskolin greater than 1,9-dideoxyforskolin, and the EC50 values were 0.24 microM, 1.8 microM, 7.1 microM, 8.8 microM, and 12.8 microM, respectively. Cytochalasin B binding to rat adipocyte membranes was inhibited by forskolin and the four analogues with the same order of potency as observed for the inhibition of glucose transport. Thus, the site of action of forskolin which is responsible for the inhibition of glucose transport and cytochasin B binding exhibits structural requirements for forskolin and its analogues that are different from those of the site responsible for the activation of adenylate cyclase.
Mol Pharmacol 1988 Apr
PMID:Activation of adenylate cyclase and inhibition of glucose transport in rat adipocytes by forskolin analogues: structural determinants for distinct sites of action. 335 86

The trematode Schistosoma mansoni possesses an adenylate cyclase that is stimulated by serotonin. During development from the newly transformed schistosomulum to the adult stage, the serotonin-stimulated activity of adenylate cyclase increases. Our results show that the apparent affinity of the receptor for serotonin is the same at all stages tested. Serotonin receptors were characterized by testing the ability of agonists and antagonists to influence cyclase activity. The order of potency of antagonists is similar to that seen in Fasciola hepatica and is different from that characteristic of mammalian serotonin receptors. The nature of serotonin receptors in S. mansoni appears to be unchanged during development from cercaria to adult. Forskolin, which activates adenylate cyclase at the catalytic subunit, increases cyclase activity at all stages of development with no change in affinity. Forskolin and serotonin act synergistically to activate cyclase, and the degree of potentiation is the same (four-fold) at all stages of development, indicating that the coupling between the serotonin receptor and the catalytic component of cyclase is fully developed in the schistosomulum. The synergism between serotonin and forskolin is characterized by an increase in Vmax with no effect on the affinity for either serotonin or forskolin. The Ka for potentiation of serotonin action by forskolin is lower than the Ka for direct activation of cyclase by forskolin. The change in adenylate cyclase activity during development from schistosomulum to adult does not appear to be attributable to a change in the nature of the serotonin receptor, the catalytic component, or the coupling mechanism between these two components. Instead, there appears to be an increase in the total receptor-coupled enzyme system.
Mol Biochem Parasitol 1987 Nov
PMID:Nature of serotonin-activated adenylate cyclase during development of Schistosoma mansoni. 343 67

The mechanism of the inhibitory action of forskolin, a plant-derived stimulator of adenylate cyclase, on glucose transport in rat adipose cells was studied. Lipolysis (glycerol release) and glucose transport activity (initial 3-O-methylglucose uptake rate) were measured after treatment of intact cells. In isolated plasma membranes, D-glucose transport and glucose-inhibitable binding of cytochalasin B, a specific labeling agent for the glucose transporter, were assayed. Forskolin inhibited insulin-stimulated glucose transport in intact cells at low concentrations which failed to stimulate lipolysis. Furthermore, the adenylate cyclase inhibitor prostaglandin E2 reduced forskolin-stimulated lipolysis but failed to reverse the transport inhibition. Therefore, the effects of the agent on lipolysis appeared to be dissociable from those on glucose transport. In plasma membrane vesicles, forskolin inhibited D-glucose transport in a competitive manner by an increase in the apparent transport Km without any detectable change in Vmax. In parallel to the transport inhibition, the agent inhibited the specific binding of cytochalasin B in both plasma membranes and low density microsomes, which contain the intracellular pool of glucose transporters in insulin-sensitive cells. The Kl of this inhibition (205 nM) was very similar to that of the inhibition of glucose transport in the membrane vesicles (203 nM). It is concluded that forskolin inhibits glucose transport by a direct interaction with the transporter (or a closely related protein) rather than through activation of adenylate cyclase.
Mol Pharmacol 1987 Mar
PMID:Forskolin inhibits insulin-stimulated glucose transport in rat adipose cells by a direct interaction with the glucose transporter. 347 May 98

Analogues of forskolin that are more soluble in water than forskolin have been synthesized and tested for their ability to interact with adenylate cyclase. These analogues are esterified with various heterocyclic amino acids at the 6 beta-hydroxyl position of forskolin or at the 6 beta-hydroxyl or 7 beta-hydroxyl position of 7-desacetyl forskolin. Analogues were tested for their ability to activate rat brain adenylate cyclase, activate detergent-solubilized rat brain adenylate cyclase, increase cyclic AMP in intact S49 wild-type cells, and inhibit the binding of 3H-forskolin to rat brain membranes. Forskolin activated rat brain adenylate cyclase with an EC50 of 4 microM and increased cyclic AMP in intact S49 cells with an EC50 of 5 microM. Analogues esterified at the 7 beta-hydroxyl position had EC50 values that ranged from 4 microM to 15 microM for activating adenylate cyclase in membranes and solubilized preparations, and for increasing cyclic AMP in S49 cells. Analogues esterified at the 6 beta-hydroxyl position with no acyl group at the 7 beta-hydroxyl position were generally less potent than the corresponding 7-acyl analogues with EC50 values that ranged from 30 microM to 100 microM. Interestingly, the diacyl analogues of forskolin containing an acetate group at the 7 beta-hydroxyl position and esterified with heterocyclic amino acids at the 6 beta-hydroxyl position were very potent at stimulating adenylate cyclase, with EC50 values that ranged from 1 microM to 25 microM. The 7-acyl analogues and the 6,7-diacyl analogues inhibited the binding of 3H-forskolin to rat brain membranes with IC50 values that ranged from 20 microM to 70 microM, while the 6-acyl analogues had much higher IC50 values that ranged from 100 nM to 375 nM. Aqueous solutions of forskolin were also produced by dissolving forskolin in solutions of hydroxypropyl-gamma-cyclodextrin. These aqueous solutions of forskolin were equipotent with alcoholic solutions of forskolin in stimulating adenylate cyclase. In conclusion, water-soluble derivatives of forskolin may be useful for increasing cyclic AMP in broken cell preparations or in intact cell preparations where the presence of organic solvents, which are necessary to solubilize forskolin, are detrimental. Alternatively, aqueous solutions of forskolin can be produced by dissolving forskolin in solutions of hydroxypropyl-gamma-cyclodextrin.
Mol Pharmacol 1987 Jul
PMID:Stimulation of adenylate cyclase by water-soluble analogues of forskolin. 360 Jun 14

The catalytic unit (C) of cardiac adenylate cyclase was resolved from the guanine nucleotide-binding regulatory protein (G/F) by fractionation of Lubrol 12A9 extracts with 33% saturated (NH4)2SO4 and by gel filtration in the presence of 3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate (CHAPS). Catalytic activity in both preparations was supported by Mg2+ and Mn2+, Vmax values being 12 fold higher in the presence of the latter cation. NaF-activated preparations were also subjected to gel filtration in the presence of CHAPS. In this case, both the catalytic activity and G/F emerged in the activated state. G/F could be deactivated by dialysis of the preparation in the absence of NaF; the catalyst however remained activated following dialysis. NaF sensitivity was reconstituted in C by nonactivated and NaF-activated preparations of G/F isolated by gel filtration. Reconstitution was dependent upon the amount of both G/F and C in the assay. Nonactivated G/F also reconstituted guanine nucleotide sensitivity in C. Catalytic activity was thermally labile, but was stabilized at 25 degrees C by substrate (Mn2+ ATP). C was stimulated up to 25-fold by forskolin. The NaF-activated catalyst resolved by gel filtration was relatively insensitive to this agent. Forskolin, however, augmented NaF-sensitivity by both non-activated and NaF-activated G/F provided it was added to the assay before G/F. Similarly, forskolin augmented guanine nucleotide sensitivity of nonactivated G/F in the presence of GTP gamma S. The P site agent 2',5'-dideoxyadenosine (DDA) was a weak inhibitor of nonactivated C, but a powerful inhibitor of C stimulated by forskolin or activated by G/F in the presence of NaF. In all respects C precipitated by (NH4)2SO4 appeared to be identical with that resolved by gel filtration. Ammonium sulfate precipitation, because of its simplicity, speed, relatively good yield, and adaptability for large scale operation, may be the preferred method for preparing cardiac C for purification studies
J Mol Cell Cardiol 1985 Feb
PMID:Resolution and properties of the catalytic unit of cardiac adenylate cyclase. 387 44

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA, an activator of C-kinase), the cation ionophore A23187, forskolin (an activator of adenylate cyclase) and thyrotropin-releasing hormone (TRH) on prolactin release from anterior pituitary cells in primary culture were investigated and compared to the effects of these same agents on prolactin release from GH4C1 cells. In both GH4C1 cells and primary pituitary cultures, 100 nM TRH increased prolactin release 3- to 5-fold within 4 min after the stimulation started. This peak response was followed by a fall to a sustained increased rate of release approximately 1.5-fold above the basal rate. The decline after the early peak was slower in primary cultures than in GH4C1 cells. Addition of 20 microM A23187 to primary cultures caused a rapid 2- to 4-fold increase in release that fell to basal values within 12 min after the stimulation started. In GH4C1 cells, A23187 caused a rise in prolactin release of less than 2-fold that was sustained longer than the rise seen in primary cultures. Perifusion of either type of cells with 50 nM TPA caused a rapid 2- to 2.5-fold increase in release that also was sustained for 30 min or more in both types of cells. Perifusion with combined TPA and A23187 caused a 3- to 5-fold increase in rate of release from each cell type that declined rapidly to a 2-fold sustained release in primary cultures, and that declined more slowly in GH4C1 cells. Forskolin, 1 microM, had only a small effect by itself, but potentiated the effect of TPA or combined TPA and A23187 in both types of cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1985 Nov
PMID:Comparison of patterns of prolactin release in GH4C1 cells and primary pituitary cultures. 393 15


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