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)

Isometric contractions of rabbit isolated aortic spirals were induced by noradrenaline (1 microM), potassium chloride (51 mM) or phorbol-12,13-dibutyrate (1 microM). A cumulative concentration-response curve for adenosine, N-ethylcarboxamidoadenosine (NECA), verapamil, sodium nitroprusside, isoprenaline or forskolin was then constructed. Sodium nitroprusside displayed selectivity towards noradrenaline- compared with potassium-contracted tissues. In contrast, verapamil selectively relaxed the potassium-contracted tissues. Adenosine preferentially relaxed the noradrenaline-contracted aorta. Adenosine, in the presence of the transport inhibitor dipyridamole (10 microM), and NECA were without effect upon potassium-contracted tissues. This absolute selectivity for noradrenaline-contracted aortas indicates that adenosine A2-receptor agonists do not interfere with calcium influx through voltage-operated channels but inhibit calcium influx via receptor-operated channels or its intracellular release. The inhibition by dipyridamole of a small relaxation by adenosine in potassium-contracted tissues indicates that this was due to stimulation of an additional intracellular site. The selectivity profile of adenosine and NECA was similar to that of forskolin and isoprenaline indicating that their relaxations were due to a common activation of adenylate cyclase and cAMP accumulation. Only sodium nitroprusside- and forskolin-relaxed aortas contracted with phorbol dibutyrate. Adenosine and NECA also failed to cause relaxation of noradrenaline-contracted aortas preincubated with the phorbol ester indicating that it may desensitize A2-receptors.
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PMID:Comparison of adenosine receptor agonists with other vasodilators on noradrenaline-, potassium- and phorbol ester-contracted rabbit aorta. 176 74

Adenosine is now considered as a major regulatory agent in the mammalian central nervous system. Its actions are mediated by specific receptors which are coupled with an adenylate cyclase system via a G protein. The postnatal development of adenosine A1 receptors was studied by quantitative autoradiography using [3H]N6-cyclohexyladenosine, a potent receptor agonist in 42 rat brain structures. The coupling of these sites to G proteins was examined by measuring the effects of in vitro addition of guanylyl-5'-imidodiphosphate, a stable analogue of guanosine triphosphate, on N6-cyclohexyladenosine binding. [3H]N6-Cyclohexyladenosine-specific binding was quite low at birth, around 10% of adult levels, and exhibited a rather homogeneous distribution pattern, except in thalamic nuclei. Data showed a sequential development of adenosine A1 receptors in relation to the time course of maturation of cerebral structures with a proliferation peak which paralleled rapid brain growth. The time period by which adult levels are reached differed according to the cerebral region studied. N6-Cyclohexyladenosine-specific binding sites appeared to be functionally linked to G proteins in all structures and at all postnatal stages. However, the potency of guanylyl-5'-imidodiphosphate to displace N6-cyclohexyladenosine binding was significantly lower before 5 days of age, suggesting functional changes during postnatal maturation in cerebral pathways modulated by adenosine.
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PMID:Quantitative autoradiographic study of the postnatal development of adenosine A1 receptors and their coupling to G proteins in the rat brain. 190 87

We have previously shown that adenosine, acting at an A1 receptor, contracts the smooth muscle of virgin guinea pig uterus (M. A. Smith, I. L. O. Buxton, and D. P. Westfall. J. Pharmacol, Exp. Ther. 247: 1059-1063, 1988) and is not coupled to the expected inhibition of adenylate cyclase (M. A. Smith, J. L. Silverstein, D. P. Westfall, and I. L. O. Buxton. Cell. Signal. 1: 357-365, 1989). To probe the importance of contractile actions of adenosine in uterine smooth muscle and to further characterize the signal transduction pathway involved in A1-receptor action, we have studied the adenosine receptor and its coupling in pregnant guinea pig myometrium. Adenosine agonist and antagonist radioligands bind to saturable sites of the A1 subtype homogeneously distributed in the smooth muscle of pregnant guinea pig uterus. Agonist competition of antagonist radioligand binding in both the absence and presence of guanine nucleotide reveals high and low agonist affinity states of the receptor. Pretreatment of tissues with pertussis toxin (PTx) shifts the high-affinity sites to a lower affinity but does not affect low-affinity sites, whereas agonist competition in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) is indistinguishable from the control, which is consistent with coupling of A1 receptors to both PTx-sensitive and PTx-insensitive GTP-binding proteins. Adenosine receptor inhibition of adenylate cyclase activity is prevented after pretreatment of the tissue with PTx, whereas increased inositol phosphate production is not. The data presented here are consistent with coupling of the A1 receptor to dual effectors in the pregnant state of the smooth muscle. The unique action of an A1 receptor to contract mammalian smooth muscle and the appearance, only in the pregnant state, of coupling to adenylate cyclase inhibition suggest a role for adenosine in parturition biology.
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PMID:Smooth muscle adenosine A1 receptors couple to disparate effectors by distinct G proteins in pregnant myometrium. 190 2

Lipolysis in rat adipocytes is controlled by the hormonally mediated stimulation and inhibition of adenylate cyclase. This dual regulation involves stimulatory (Gs) and inhibitory (Gi) GTP-binding proteins which control cAMP production in a GTP dependent manner. Adenosine, acting via the A1 receptor-Gi complex provides tonic regulation of adenylate cyclase and lipolysis in rat adipocytes. Adipocytes prepared from young obese Zucker (fa/fa) rats exhibit less stimulation (or greater inhibition) in response to adenosine deaminase, alone or in combination with lipolytic hormones, as compared with their lean littermates. Adenylate cyclase, measured in membranes prepared from obese adipocytes, showed decreased sensitivity to activation by low concentrations of GTP and was not inhibited by higher concentrations of the guanine nucleotide which, in lean control rats results in a biphasic activity curve. Adenosine A1 receptor binding, measured in these same membranes, demonstrated an increased sensitivity to activation by the GTP analogue, guanylyl imidodiphosphate. The presence of the analogue results in the dissociation of the receptor-Gi complex and conversion to the low affinity form in a greater proportion of receptors in the obese membranes. These results are consistent with an increased sensitivity to adenosine mediated inhibition of adenylate cyclase and lipolysis in the fat cells of the young obese (fa/fa) Zucker rat.
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PMID:Winner of the 1988 NAASO Young Investigator Award. Regulation of fat cell adenylate cyclase in young Zucker (fa/fa) rats: alterations in GTP sensitivity of adenosine A1 mediated inhibition. 196 33

The effects of adenosine receptor stimulation on the contractile force of rabbit isolated left atrial preparations in the absence and presence of cAMP-generating and cAMP-independent agonists were investigated. Adenosine and the stable adenosine analogues 5'-(N-ethyl)carboxamido adenosine (NECA) and (-)-N6-phenylisopropyladenosine (R-PIA) produced a concentration-dependent direct negative inotropic effect. Responses to NECA and R-PIA were insensitive to atropine and were shifted to the right by the adenosine receptor antagonist 3-isobutyl-1-methyl xanthine (IBMX). NECA and R-PIA were found to reverse positive inotropic responses of left atria to the beta-adrenoceptor agonist, isoproterenol, but were less effective at reversing positive inotropic responses to the adenylate cyclase activator, forskolin, and were almost ineffective at reversing positive inotropic responses to alpha-adrenoceptor stimulation. Neither NECA nor R-PIA had a significant effect on basal cAMP levels or on cAMP levels elevated by isoproterenol in rabbit left atria. Similarly, R-PIA had no significant effect on basal cAMP levels or isoproterenol-induced increases in cAMP in the presence of adenosine deaminase to remove the influence of endogenous adenosine. Pretreatment of rabbits with 1.75 micrograms/kg pertussis toxin attenuated both the direct negative inotropic response of left atria to NECA and responses to NECA in the presence of isoproterenol and forskolin to a similar extent. Pretreatment of left atrial preparations with the potassium channel antagonist 4-aminopyridine resulted in a dose dependent attenuation of responses to NECA alone and in the presence of isoproterenol and forskolin. These data suggest that adenosine receptors in rabbit left atria are not coupled to adenylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The interaction of adenosine analogues with cAMP-generating and cAMP-independent positive inotropic agents in rabbit left atrium. 196 30

1. In intact ventricular preparation, adenosine has been shown to reduce the beta-adrenoceptor-induced increase in contraction (the anti-adrenergic effect). In the present study we have investigated this effect of adenosine on isolated ventricular myocytes from failing human heart and normal guinea-pig and rat heart. 2. Adenosine in the absence of beta-adrenoceptor-mediated stimulation had no effect on contraction in human and guinea-pig myocytes but produced a variable effect in rat myocytes. 3. 8-Cyclopentyl 1,3-dipropylxanthine (CPX), a selective A1-receptor antagonist, antagonised the anti-adrenergic effect of adenosine in guinea-pig myocytes. 4. The anti-adrenergic effect of adenosine was greater in guinea-pig than rat myocytes and even more pronounced in cells isolated from failing human heart. 5. Pertussis toxin-pretreatment at 35 degrees C of guinea-pig and human myocytes abolished the anti-adrenergic effect of adenosine. Longer exposure to higher concentrations of pertussis toxin was required for complete abolition in human compared to guinea-pig cells. 6. These results support the suggestion that the adenosine receptors mediating the anti-adrenergic effect of adenosine are of the A1 subtype and are coupled to the inhibitory guanine nucleotide binding protein, Gi/Go. 7. Pertussis toxin pretreatment increased the sensitivity of guinea-pig myocytes to isoprenaline in the absence of adenosine; the EC50 value was decreased by a factor of 10. This suggests that Gi may exert a tonic inhibitory effect on the beta-adrenoceptor/adenylate cyclase interaction in normal myocardium.
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PMID:The anti-adrenergic effect of adenosine and its blockade by pertussis toxin: a comparative study in myocytes isolated from guinea-pig, rat and failing human hearts. 197 12

Field electrical stimulation (ES), K+ (50 mM) or ionophore X-537A (0.01 mM) induced tritium release from cat cerebral arteries preincubated with [3H]noradrenaline (NA). Adenosine and AMP (0.5 mM) did not modify tritium release caused by ionophore X-537A, but these agents and ATP (0.5 mM) significantly reduced that elicited by ES and K+; this reduction was antagonized by 1-methyl-3-isobutylxanthine (MIX; 0.05 mM). Inosine (0.5 mM) and the agonist of purinergic A2-receptors, 5'N-ethyl-carboxamide adenosine (NECA; 0.5 mM) had no effect, but the agonist of purinergic A2-receptors L-N6-phenylisopropyl adenosine (L-PIA; 0.1 mM) diminished tritium efflux caused by ES and K+. The adenosine inhibition of ES-induced radioactivity release was not affected by indomethacin (0.05 mM). MIX (0.05 mM) increased tritium release evoked by ES and K+. Agents that increase intracellular cyclic (c)AMP levels, such as dibutyryl cAMP (0.5 mM), the phosphodiesterase inhibitor Ro 20-1724 (0.1 mM), and the activators of adenylate cyclase, forskolin (0.005 mM) and NaF (2 mM) reduced tritium secretion elicited by ES and K+. However, the intracellular increase of cyclic GMP (cGMP) caused by 8-Br-cGMP did not affect this secretion. Dipyridamole (0.05 mM) and the adenosine deaminase inhibitor erythro-9-2-hydroxy-3 nonyl adenosine (EHNA; 0.1 mM) also produced inhibition of tritium secretion elicited by ES and K+. Dipyridamole reduced both the uptake of [3H]NA and [3H]adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of presynaptic purinoceptors and cyclic AMP on the noradrenaline release in cat cerebral arteries. 198 Feb 88

We utilized the closed window technique to study the in vivo responses of rat pial arterioles to superfused adenosine agonists. Adenosine and its analogs dilated pial arterioles and exhibited the following order of potency: 5'N-ethylcarboxamide adenosine (NECA) greater than 2-chloroadenosine (2-CADO) greater than adenosine = R-N6-phenylisopropyladenosine (R-PIA) = S-PIA greater than N6-cyclohexyladenosine (CHA). This potency profile suggests that cerebral vasodilation is mediated through the A2 receptor. Forskolin (10(-9) M) potentiated the vasodilation caused by 10(-6) M NECA, thus implicating adenylate cyclase activation during NECA-induced vasodilation and providing further support for involvement of the A2 receptor.
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PMID:Effects of topical adenosine analogs and forskolin on rat pial arterioles in vivo. 198 7

Adenosine exerts numerous effects in the central and autonomic nervous systems, most of which seem to be receptor mediated. Several studies have revealed two distinct receptors, based upon effects of adenosine on adenylate cyclase activity, designed A1 or A2 according to whether the cyclase is inhibited or activated. However, since not all adenosine receptors are linked to adenylate cyclase some authors base their classification on the rank orders of potencies of adenosine analogues in eliciting responses. The purine seems to function as a modulatory substance in the heart, blood, ileum, vas deferens, and adipose tissue. In addition, important responses to exogenously added adenosine are also induced in the bronchi, urinary bladder, taenia coli, parietal cells of the stomach and renin secretion. Adenosine and its analogues elicit anticonvulsant responses, sedation and hypothermia through their actions in the central nervous system. The mechanisms by which adenosine elicits its responses have not been clearly established. The activation of A1 receptors depresses the release of neurotransmitters and inhibit the influx of Ca into nerve terminals. Whether this effect is induced by interaction with Ca channels or by impairment of Ca dependent processes associated with neurotransmitter release is unknown. In the rat heart adenosine inhibits adenylate cyclase and subsequently the phosphorylation of L-type Ca channels, resulting in a decrease of calcium influx in the muscle cell. The responses to activation of A2 receptors in smooth muscle consist in relaxation presumptively by an increase of K current which would hyperpolarize the cell.
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PMID:[Adenosine: physiological and pharmacological actions]. 215 91

Adenosine and its nucleotides participate in the regulation of various functions in the nerve system and in some internal organs. These purines are released from a variety of nervous and non-nervous cellular sources. Adenosine receptors are situated extracellular; they mediate some effects of the adenosine and are coupled negatively (A1 adenosine receptors) and positively (A2 adenosine receptors) to adenylate cyclase. The physiological effects of adenosine are inhibitory; they are exerted synaptically and extrasynaptically. The main synaptic modulatory effect is the presynaptic inhibition of the excitatory and inhibitory neurotransmitters release. Postsynaptically adenosine modulate the answer to neurotransmitter effects. ATP functions probably as co-transmitter or transmitter in the non-adrenergic non-cholinergic autonomic neurons. Neuromodulatory and the majority of metabolic adenosine effects are antagonized by methylxanthines. Exogenous substances can influence the molecular mechanisms of adenosine systems; some of the induced pharmacodynamical effects could be of therapeutic interest. Drug-interactions with adenosine systems can cause side effects.
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PMID:[Purinergic neuromodulation]. 215 63


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