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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibition of insulin-stimulated glucose transport by lipolytic agents was studied in isolated rat adipose cells. Two different mechanisms for the inhibition of glucose transport by lipolytic hormones and agents were distinguished by use of the antilipolytic agent prostaglandin E2 (PGE2). The inhibition of glucose transport induced by lipolytic hormones such as glucagon, catecholamines or ACTH in the presence of adenosine deaminase was antagonized by PGE2. In contrast, inhibition of hexose transport by alkylxanthines was only partially (20-30%) attenuated by PGE2, although the eicosanoid had antagonized cyclic AMP accumulation and stimulation of lipolysis in response to all tested lipolytic agents. The inhibition of glucose transport by IBMX was immediate, whereas the lipolytic hormones (isoprenaline and ACTH) exhibited a latency of 2-3 min. In addition, the inhibition induced by the lypolytic hormones disappeared after cooling of the cells to 22 degrees C, at which temperature IBMX was still inhibitory. Thus, the PGE2-sensitive component of the effect of lipolytic agents on glucose transport appears to be mediated by adenylate cyclase or its subunits Ns/Ni. The PGE2-insensitive effect of alkylxanthines probably reflects a direct interaction of the agents with a regulatory site at the transporter or a related protein.
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PMID:Prostaglandin E2 differentiates between two forms of glucose transport inhibition by lipolytic agents. 244 31

We studied the effects of adenosine and adenosine derivatives on adenylate cyclase activity in cultured endothelial cells from bovine pulmonary artery. Basal and stimulated enzyme activities were measured in membrane preparations using [alpha-32P]ATP as the substrate and chromatographic isolation of formed [32P]cAMP. Basal cyclase activity was 11 +/- 1 (mean +/- SEM) pmol/mg protein/min. Forskolin, 5'-guanylylimidodiphosphate (Gpp(NH)p) and (-)isoproterenol stimulated adenylate cyclase in a concentration-dependent manner, producing maximal stimulations of three, seven and four times the basal activity respectively. In the presence of adenosine deaminase, cyclohexyladenosine, an A1 agonist, had no effect on basal and forskolin- or Gpp(NH)p-stimulated activities, whereas 5'-(N-ethyl)-carboxamidoadenosine (NECA), an A2 agonist, had a small stimulatory effect (52% increase over basal). In the presence of IBMX, adenosine and two P-site agonists, 2',5'-dideoxyadenosine (DDA) and 2'-deoxyadenosine-3'-monophosphate (2'-deoxy-3'-AMP), inhibited forskolin (30 microM)-stimulated adenylate cyclase activity with an order of potency of 2'-deoxy-3'-AMP greater than DDA greater than adenosine. DDA and 2'-deoxy-3'-AMP were also able to inhibit cyclase activity stimulated by Gpp(NH)p (10(-5)M) or isoproterenol (10(-6)M) with the same order of potency. Only 2'-deoxy-3'-AMP inhibited the stimulated adenylate cyclase activity by more than 50% (IC50 = 19-32 microM). These findings indicate that (1) long-term cultured endothelial cells from bovine pulmonary artery express A2 and beta-adrenergic receptors which stimulate adenylate cyclase activity through Gs transducer proteins, and (2) the natural compound and P-site agonist, 2'-deoxy-3'-AMP, is a potent inhibitor, and possibly a natural regulator, of adenylate cyclase activity in this tissue.
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PMID:Modulation of adenylate cyclase activity in cultured bovine pulmonary arterial endothelial cells. Effects of adenosine and derivatives. 246 5

Adenosine inhibits TSH-stimulated [3H]thymidine incorporation into DNA in FRTL5 thyroid follicular cells by both inhibiting cAMP generation and acting at a locus beyond adenylate cyclase. On the other hand, adenosine markedly potentiates DNA synthesis in FRTL5 stimulated by insulin-like growth factor-I (IGF-I). The mechanisms of this latter effect are unknown, but require the coincubation of adenosine and IGF-I and not mediated by an increase in intracellular cAMP concentration. Adenosine increases the maximal response of FRTL5 to [3H]thymidine incorporation stimulated by IGF-I and increases the sensitivity of FRTL5 to IGF-I. These effects of adenosine are reflected by an increase in nuclear labeling as well as by an increase in [3H]thymidine incorporation into DNA. Adenosine also plays a role as an autocrine growth factor in FRTL5, since adenosine deaminase increases the response of these cells to TSH. The effects of adenosine on both TSH- and IGF-I-stimulated DNA synthesis are shared by guanosine and inosine, although with different potencies for the various guanine nucleosides. Inosine potentiates IGF-I-stimulated DNA synthesis, but inhibits TSH-stimulated DNA synthesis only weakly. Adenosine interacts with multiple receptors and with multiple postreceptor pathways in FRTL5 to produce divergent effects on the control of cell replication by two growth factors (TSH and IGF-I) that act through different postreceptor pathways.
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PMID:Adenosine has divergent effects on deoxyribonucleic acid synthesis in FRTL5 cells: inhibition of thyrotropin-stimulated and potentiation of insulin-like growth factor-I-stimulated thymidine incorporation. 247 35

We wished to determine whether adenosine, a purine nucleotide, modulates activity of respiratory cilia and, to this end, we studied cultured rabbit tracheal epithelium in response to adenosine and related substances in vitro. Ciliary beat frequency (CBF) as determined by a photoelectric method was depressed by adenosine (10(-3) M), the maximal decrease from the baseline value (965 +/- 29 beats/min, mean +/- SE) being 31.6 +/- 5.0% (p less than 0.001). The adenosine A2-receptor agonist N-ethylcarboxamide adenosine had only a small effect on ciliary activity, whereas other adenosine analogs elicited decreases in CBF in a dose-dependent fashion. The order of potency of cilia-inhibitory action was N-cyclohexyladenosine (an agonist for adenosine A1-receptor) greater than phenylisopropyladenosine greater than adenosine greater than N-ethylcarboxamide adenosine. Intracellular cyclic AMP (cAMP) levels were decreased by 10(-3) M adenosine from 39.2 +/- 6.5 to 25.3 +/- 4.8 pM/mg protein (p less than 0.05). The effect of adenosine on CBF was enhanced by dipyridamole, an adenosine uptake inhibitor, and by deoxycoformycin, an adenosine deaminase inhibitor. The adenosine-induced decreases in CBF and cAMP content were reversed by 8-phenyltheophylline, an adenosine receptor antagonist. These results suggest that there is an adenosine A1-receptor on rabbit tracheal epithelium that inhibits adenylate cyclase, which may result in the impairment of respiratory ciliary activity, and that adenosine-induced ciliary inhibition may be modulated by adenosine uptake and its catabolism by airway epithelial cells.
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PMID:Adenosine-mediated cyclic AMP-dependent inhibition of ciliary activity in rabbit tracheal epithelium. 253 29

Purine release and prostaglandin (PG) outflow were simultaneously evaluated from untreated glial primary cultures of rat striatum, at rest and under field electrical stimulation. Purine release was also assayed from sister cultured cells in which a suitable pharmacological treatment with 1 x 10(-6) M dexamethasone or 1 x 10(-4) M indomethacin had produced a complete inhibition of the phospholipase A2-prostaglandin (PLA2-PG) system. Purine release from untreated cells seems to be regulated by specific receptor sites for released adenosine (Ado); A1 receptors exert an inhibitory control on purine release while A2 receptors facilitate it. PG release appears to be related to A1-mediated Ado activity, since culture treatment with 1 x 10(-10) M 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or 1 x 10(-4) M N-ethylmaleimide (NEM), A1 receptor inhibitory agents able to increase purine release, induced a significant reduction of the evoked PG outflow. Purine amount, released from glial cells with inhibited PLA2-PG system, was remarkably greater than that one assayed from control cultured cells. In so treated cultures, no additive effect, NEM-induced, was detected, while the addition of a mixture of PGs partially reduced the increased purine outflow. An electrically evoked cAMP accumulation, significantly greater than that found in controls, was even detected in cultured cells with inhibited PLA2-PG system. Since 10 micrograms/ml adenosine deaminase (ADA) reduced while DPCPX enhanced the evoked cAMP accumulation, it seems partially due to released Ado and accounts for a prevalent A2-stimulating rather than an A1-inhibitory control on adenylate cyclase activity. Thus, in cultured glial cells, the PLA2-PG system, likely linked to A1 receptor sites, concurs to control purine release and seems to affect less directly cAMP accumulation.
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PMID:Influence of PLA2-PG system on purine release and cAMP content in dissociated primary glial cultures from rat striatum. 254 40

Adenosine agonists cause a marked stimulation in cyclic AMP accumulation in whole human retinal pigment epithelial (RPE) cells in the presence of adenosine deaminase and papaverine, a phosphodiesterase inhibitor. N-Ethylcarboxamidoadenosine (NECA) stimulates cyclic AMP accumulation 16.1-fold above basal with an EC50 of 2.5 x 10(-7) M. It is also an effective (1.9-fold) stimulator of adenylate cyclase activity in RPE membrane preparations and a modest (1.22-fold) stimulator in the presence of forskolin in RPE cell membranes prepared from freshly isolated porcine RPE. N6-Cyclopentyladenosine (CPA) and N6-phenylisopropyladenosine (PIA) also increase cyclic AMP levels with EC50s of 4.9 x 10(6) M (8.9-fold above basal) and 3.5 x 10(-6) M (8.0-fold above basal) respectively. This potency order (NECA greater than PIA greater than CPA) is typical of A2-adenosine receptors. The relatively A1-selective agonists 10(-7) M indicating that RPE cells do not have A1-receptors which inhibit adenylate cyclase. Three adenosine receptor antagonists, BW-A1433U, 8-cyclopentyltheophylline and 8-sulfophenyltheophylline, blocked the NECA-induced stimulation of cyclic AMP accumulation with IC50s of 0.36 microM, 1.5 microM, and 75 microM respectively. Since alteration of cAMP levels has been demonstrated to affect several RPE functions, including cell migration, resorption of subretinal fluid, and phagocytosis, adenosine may play a significant regulatory role in RPE.
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PMID:Human retinal pigment epithelial cells in culture possess A2-adenosine receptors. 254 54

The effects of the adenosine receptor agonists (-)-N6-phenylisopropyladenosine (PIA) and 5'-N-ethylcarboxamideadenosine (NECA) on the force of contraction, adenylate cyclase activity and cAMP content in the presence of isoprenaline (Iso) were studied in ventricular preparations of the guinea-pig heart. Only in the presence of adenosine deaminase (ADA) and 50 mM sodium chloride, i.e. under 'optimal' conditions, did PIA and NECA reduce the Iso-stimulated adenylate cyclase activity in broken cell preparations, with a maximal effect of about 25%. In electrically driven (1 Hz) papillary muscles from guinea-pigs, both compounds concentration dependently reduced the Iso-stimulated force of contraction maximally by about 50% in the presence of ADA (1 microgram/ml). cAMP was measured in the same preparations. Low concentrations (0.1-1 microM) of PIA reduced the cyclic AMP content while higher concentrations increased the cyclic AMP content. The negative inotropic effect of NECA was accompanied by a concentration-dependent increase in the cyclic AMP content. We conclude that the negative inotropic effect of PIA in the presence of Iso is only in part due to a decrease in the cyclic AMP content resulting from inhibition of adenylate cyclase activity. Such an effect was only detected in the presence of ADA so that endogenous adenosine can obviously mask small effects of PIA on adenylate cyclase activity or the cyclic AMP content. In addition, the negative inotropic effect of NECA in the presence of isoprenaline was not accompanied by a reduction but an increase in the cyclic AMP content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of adenosine analogues on force and cAMP in the heart. Influence of adenosine deaminase. 254 33

We have recently shown the presence of adenosine receptors coupled to adenylate cyclase in anterior pituitary and in the present studies we have investigated the effects of adenosine on ACTH release. The 'R'-site specific analogs of adenosine such as N-Ethylcarboxamide adenosine (NECA), L-N6-phenylisopropyl adenosine (PIA), 2-chloro-adenosine (2-Cl-Ado) all stimulated ACTH release in a dose-dependent manner. NECA was the most potent analog and stimulated ACTH release by about 170% with an apparent Ka of 0.1 microM, whereas PIA and 2-Cl-Ado were less potent and stimulated the release by about 110% and 125% with an apparent Ka of 0.2 and 0.4 microM respectively. The stimulation of ACTH release by NECA was inhibited by 3-isobutyl-1-methylxanthine (IBMX). On the other hand, adenosine deaminase (ADA) treatment of the cells also stimulated ACTH release as well as adenylate cyclase activity by about 2-fold, suggesting that endogenous adenosine plays an inhibitory role in the release of ACTH. Other agents, such as corticotropin-releasing factor (CRF), vasoactive intestinal peptide (VIP) and forskolin (FSK) also stimulated ACTH release from these cells. In addition, the stimulation by an optimal concentration of NECA was almost additive with maximal stimulation caused by VIP and FSK. These data suggest that adenosine modulates ACTH release from anterior pituitary through its interaction with adenosine receptors coupled to adenylate cyclase.
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PMID:Adenosine regulates the release of adrenocorticotropic hormone (ACTH) from cultured anterior pituitary cells. 255 Jul 86

The effect of neuropeptide Y (NPY) on cell contractions of ventricular myocytes isolated from the adult rat heart was investigated. Maximum changes in cell length (dL) during stimulated (0.5 Hz) contractions were determined in presence of the phosphodiesterase inhibitor Ro 20-1724 (0.5 mM) and adenosine deaminase (5 U/ml). Under these basal conditions NPY (10(-6) M) reduced dL by 39% of control. Isoproterenol (10(-6) M) increased dL by 105% of control; the EC50 was 2 x 10(-9) M. NPY reduced the increase in dL achieved by isoproterenol in a dose dependent manner. The IC50 value was 1 x 10(-9) M and NPY (10(-6) M) produced complete inhibition. In the absence of the phosphodiesterase inhibitor the IC50 was 4 x 10(-9) M. The EC50 of isoproterenol and IC50 of NPY producing accumulation of cAMP in myocytes (Millar et al. 1988) exceeded the respective values of dL by one order of magnitude. Prior treatment of the myocytes with pertussis toxin abolished the potency of NPY to antagonize the increase in dL by isoproterenol while not interfering with the response to the beta-agonist. These results demonstrate a negative inotropic effect of NPY on the ventricular myocardial cell. Complete abolition of the effect of NPY by pertussis toxin indicate that this effect is mediated by a sarcolemmal receptor for NPY linked to adenylate cyclase via an inhibitory guanine nucleotide binding protein.
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PMID:The negative inotropic effect of neuropeptide Y on the ventricular cardiomyocyte. 255 54

We have examined the effects of R-phenylisopropyladenosine (R-PIA) and other adenosine analogues on basal, prostaglandin E1 (PGE1)- and forskolin-stimulated cyclic AMP (cAMP) formation in intact N1E-115 neuroblastoma cells, to determine whether the cells contain A1 adenosine receptors that are negatively coupled with adenylate cyclase. Basal levels of cAMP (68 +/- 7 pmol/mg protein; mean +/- SE, N = 15) were not altered by low concentrations of R-PIA. The apparent lack of inhibition was not due to increases in cAMP due to activation of a stimulatory A2 receptor by endogenously-synthesized adenosine. By comparison, low levels of R-PIA did reduce significantly (P less than 0.05) PGE1-dependent increases in cAMP formation (maximum response to PGE1, 972 +/- 77 pmol cAMP/mg protein; EC50 for PGE1, 0.2 microM). Inhibition was dose dependent, and resulted in a 30-50% maximum reduction in production stimulated by PGE1. Nanomolar concentrations of R-PIA elicited half-maximal inhibition; the inhibitory response was blocked by 8-phenyltheophylline (8-PT). The order of potencies of several adenosine analogues in eliciting this response suggested that inhibition was mediated by an A1 adenosine receptor. Examination of the effects of R-PIA on forskolin-stimulated cAMP formation yielded several interesting findings. First, stimulation by the diterpene by itself was blocked by both adenosine deaminase (ADA) and 8-PT (40 and 25% inhibition respectively). Low concentrations of R-PIA (less than 10(-6) M) had no effect on forskolin-stimulated cAMP production. At higher levels (greater than or equal to 10(-6) M) the analogues acted synergistically with the diterpene, to yield cAMP levels that were up to 3-fold higher than the additive effect of the two agents. Potentiation was stereospecific, Ca2+ dependent, and was blocked by 8-PT. The results of this study suggest that, in N1E-115 neuroblastoma cells, inhibitory A1 receptors are not stimulated in response to non-specific elevations in cAMP, but are associated with specific stimulatory receptors such as those activated by PGE1.
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PMID:Effects of adenosine analogues on basal, prostaglandin E1- and forskolin-stimulated cyclic AMP formation in intact neuroblastoma cells. 255 19


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