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)

[3H]Acetylcholine release elicited with 360 pulses/3 Hz from slices of rabbit hippocampus is facilitated in the presence of the muscarine (M) receptor antagonist atropine (indicating the existence of autoinhibition) and diminished by the M receptor agonists carbachol and oxotremorine. N-Ethylmaleimide (30 microM) and pertussis toxin (8 micrograms/ml) counteracted antagonist-induced facilitation and agonist-induced inhibition of release, suggesting that a pertussis toxin-sensitive GTP-binding protein is involved in the chain of events mediating activation of M receptors to inhibition of release. Neither 8-bromo-cyclic AMP (300 microM), a membrane analogue of cyclic AMP, nor rolipram (10 microM), a phosphodiesterase inhibitor, affected electrically evoked release of [3H]acetylcholine. They also did not influence the oxotremorine-induced inhibition of transmitter release. In conclusion, no evidence was found for the assumption that activation of M autoreceptors is linked to inhibition of adenylate cyclase.
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PMID:Muscarine receptors regulating electrically evoked release of acetylcholine in hippocampus are linked to pertussis toxin-sensitive G proteins but not to adenylate cyclase. 836 Jun 71

Ductal elements within salivary glands are responsible for modifying the electrolyte composition of primary saliva secreted by the acini. To study the mechanism and regulation of the transport processes involved requires a suitable preparation of functional ducts. To this end we have isolated intralobular ducts from rabbit mandibular salivary glands using the technique of tissue dissociation and microdissection. Light and electron microscopy demonstrated that the ducts corresponded ultrastructurally to striated intralobular ducts of the intact gland. Ducts could be maintained in tissue culture on polycarbonate filter rafts for up to 36 h, during which time the ends of the ducts did not usually seal. The overall resting content of ductal adenosine 3',5'-cyclic monophosphate (cyclic AMP) was 16.0 +/- 3.0 fmol mm-1 and increased dose dependently in response to stimulation with the beta-adrenoceptor agonist isoprenaline (10(-9)-10(-4) M; concentration required to produce a half-maximal response, K0.5 = 2.1 x 10(-6) M). The response to isoprenaline was blocked by the antagonist propranolol. Intracellular cyclic AMP content was also raised by the adenylate cyclase activator forskolin and by prostaglandin E2. Acetylcholine (3 x 10(-8)-10(-5) M) caused a dose-dependent and maintained rise in [Ca2+]i (K0.5 = 2.5 x 10(-7) M). This increase in [Ca2+]i could be reversed by the muscarinic antagonist atropine and appeared to result from a combination of mobilization of intracellular Ca2+ stores and entry of Ca2+ from the extracellular fluid. Noradrenaline induced only a very small, mainly transient rise in [Ca2+]i while phenylephrine failed to increase [Ca2+]i at all. Vasoactive intestinal peptide (5 x 10(-7) M) also produced a marginal, maintained rise in [Ca2+]i. Substance P, bombesin, isoprenaline, and prostaglandin E2 did not elevate [Ca2+]i. Application of the calcium ionophore ionomycin induced a substantial maintained rise in [Ca2+]i. Taken together, these results indicate that isolated and cultured striated ducts (i) possess intact beta-adrenoceptors coupled to adenylate cyclase, putative receptors for prostaglandin E2 and muscarinic receptors, and (ii) represent a viable preparation for the study of the transport mechanisms involved in the ductal modification of salivary fluid composition.
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PMID:Structural and functional characterization of striated ducts isolated from the rabbit mandibular salivary gland. 838 3

Myocardial cells are able to adapt the cardiac pump function rapidly and widely to the changing requirements of vital organs through intrinsic and extrinsic regulatory mechanisms. This regulation is achieved by alteration of [Ca2+]i mobilization, Ca2+ sensitivity of myofibrils or both. Frank-Starling's mechanism achieved by alteration of Ca2+ sensitivity and force-frequency relation, primarily due to modulation of [Ca2+]i mobilization, are important intrinsic mechanisms. As extrinsic mechanisms, catecholamines play a crucial role by activation of both beta- and alpha 1-adrenoceptors through cyclic AMP, and products of phosphoinositide hydrolysis, as messengers, respectively. Adenosine and ACh act via similar transduction processes, including Gi or Gk proteins coupled to inhibition of adenylate cyclase, or activation of K+ channels. Most of these regulations are modulated and constitute crucial pathophysiological mechanisms in chronic heart failure.
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PMID:[Signal transduction in regulation of myocardial contractility]. 839 32

1. We investigated the mechanism of signal transduction during the effect of muscarinic receptor stimulation on Ca2+ transients, tension, Ca2+ sensitivity and the cross-bridge cycling rate (CCR). 2. Membrane-permeable derivatives of cyclic GMP (8-bromo-cyclic GMP and dibutyryl cyclic GMP) did not cause any significant changes in the peaks of Ca2+ transients and tension and the time courses of either signal modulated by isoprenaline (Iso) (0.1 microM). 3. Nitroprusside (0.1-1 mM) likewise did not change the peaks or the time courses of Ca2+ transients and tension in the Iso-treated preparations. 4. In papillary muscles excised from ferrets treated with pertussis toxin (islet-activating protein, IAP), which is known to abolish the function of GTP-binding proteins (Gi, Go and Gt), similar changes in Ca2+ transients and tension produced by treatment with Iso (0.1 microM) were noted as in non-IAP-treated preparations. However, no effects of acetylcholine (ACh; 1 microM) on either signal were observed. 5. The relation between [Ca2+]i and tension measured during the steady state of tetanic contraction was shifted to the right by Iso (0.1 microM), and cyclic GMP derivatives (1 mM) did not change the altered relation. In the IAP-treated preparations, ACh (1 microM) did not influence the relation altered by Iso (0.1 microM). 6. Cyclic GMP derivatives (1 mM) did not alter the Iso (0.1 microM)-increased CCR measured by perturbation analysis. ACh (1 microM) did not restore the Iso-increased CCR in the IAP-treated preparations. 7. These results suggest that signal transduction in muscarinic receptor stimulation is primarily mediated by inhibition of adenylate cyclase via IAP-sensitive GTP-binding proteins, and that cyclic GMP does not play an important role in the effect of muscarinic receptor stimulation on Ca2+ transients, tension, Ca2+ sensitivity or CCR.
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PMID:Mechanism of the effects of acetylcholine on the contractile properties and Ca2+ transients in ferret ventricular muscles. 839 24

Biochemical properties of adenylate cyclase in striatal and cortical membranes have been analyzed in parallel with their regulation by cholinergic compounds. Striatal adenylate cyclase is more sensitive to forskolin, while the cortical enzyme is more stimulated by GTP. In the presence of GTP, more inhibition by acetylcholine is seen in the cortex than in the striatum. Acetylcholine inhibits striatal adenylate cyclase activity equally in the presence or absence of forskolin but has a diminished ability to inhibit forskolin-stimulated adenylate cyclase in the cortex. The greater sensitivity of cortical muscarinic receptor-coupled adenylate cyclase to EGTA and calcium indicates predominant involvement of the calcium/calmodulin-dependent subtype of the enzyme. The relative effectiveness of antagonists, demonstrating an order of potency of atropine > amitriptyline > pirenzepine > gallamine in reversing the inhibition of adenylate cyclase by acetylcholine for both brain regions, suggests predominantly m4 receptor-mediated responses. These results suggest an m4-type receptor may be coupled to subtypes of adenylate cyclase in the striatum and cortex which differ in their biochemical properties.
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PMID:A comparison of the regulatory properties of striatal and cortical adenylate cyclase. 845 Sep 35

Vasoactive intestinal peptide (VIP) is a putative neurotransmitter found in extrinsic and intrinsic nerves of the heart. VIP can be released by vagal stimulation but, contrary to ACh, causes positive chronotropic effects as a result of binding to cardiac receptors which stimulate adenylate cyclase, and thus has been implicated in vagal tachycardias. Since the rate of diastolic depolarization of sinoatrial (SA) node myocytes depends on the hyperpolarization-activated current (if), which is directly activated by cytoplasmic cAMP, we studied the action of VIP on if in myocytes isolated from the SA node of the rabbit. VIP (0.65 microM) reversibly increased if at -65 mV but had no effect at -115 mV suggesting that its primary effect was to shift the activation curve to more positive voltages. Hyperpolarizing ramp and voltage compensation protocols indicated that VIP shifts the activation curve of if by approximately 5-6 mV in the positive direction with no change in maximal conductance. This shift may be the mechanism by which VIP produces its positive chronotropic effect and supports a negative feedback role for this peptide during elevated vagal activity.
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PMID:Activation of the hyperpolarization-activated current (if) in sino-atrial node myocytes of the rabbit by vasoactive intestinal peptide. 859 36

Relaxation of the trabecular smooth muscle, which is necessary for penile erection, is controlled locally by neurotransmitters and vasoactive agents. The goal of this study was to identify and characterize muscarinic acetylcholine receptor (mAChR) subtypes expressed in cultured human corpus cavernosum smooth muscle cells (HCC SMC). Binding analysis with L-[benzilic-4,4'-3H(N)]quinuclidinyl benzilate ([3H]QNB) demonstrated the expression of specific muscarinic receptor binding sites in HCC SMC. Analysis of total RNA isolated from whole corpus cavernosum tissue and smooth muscle cells, by RNase protection assays, demonstrated the expression of mRNA transcripts for m1, m2, m3, and m4 mAChR subtypes in whole tissue and m2 and m4 subtypes in cultured cells. In situ hybridization with specific m2 and m4 probes further confirmed the expression of m2 and m4 mRNA transcripts in cultured cells. Carbachol (CCh), a nonselective cholinergic agonist, inhibited cAMP synthesis at low concentrations (0.1-1 microM) and stimulated cAMP synthesis at high concentrations (100 microM), in cultured HCC SMC. CCh (100 microM) further augmented forskolin (FSK), isoproterenol (ISO), and prostaglandin E1 (PGE1)-induced cAMP synthesis. These observations suggest that, in vivo, in HCC, ACh may activate m3 mAChR subtypes on endothelial cells or m2 and m4 subtypes on the SMC. Although m2 and m4 are thought to inhibit adenylate cyclase (AC), the augmentation of cAMP synthesis by high concentrations of CCh in SMC suggests an alternative mechanism of coupling to G-proteins that stimulates AC activity. These studies show that HCC tissue expresses different subtypes of mAChR (m1, m2, m3, and m4), whereas cultured HCC SMC express m2 and m4 subtypes. It is suggested that m2 and m4 receptor subtypes may play an important role in maintaining trabecular smooth muscle tone in vivo. The augmentation of FSK-, ISO, and PGE1-induced cAMP synthesis by CCh suggests possible development of a multidrug therapeutic approach to treatment of erectile dysfunction.
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PMID:Expression of functional muscarinic acetylcholine receptor subtypes in human corpus cavernosum and in cultured smooth muscle cells. 872 95

1. Isolated cannulated ventricles commenced spontaneous beating on application of perfusion pressure of 10 cm water. Complete hearts showed a fast patterned cyclical rhythm, whereas ventricles devoid of atrial material showed a continuous slow rhythm. 2. Perfused ventricles were inhibited by ACh with a threshold at 10(-8) mol l-1 and arrested at 10(-7) mol l-1, and ventricles under stimulation by 5HT could be arrested by ACh at this concentration. 3. Perfused ventricles were stimulated by 5HT, with threshold at 10(-9) mol l-1 and maximum at 10(-5) mol l-1. Metoclopramide was without affect on 5HT responses, but metitipine and methysergide did inhibit such responses suggesting that the 5HT receptor present possessed mixed properties of the vertebrate 5-HT1 and 5-HT2 receptor subtypes. 4. Ventricles were very sensitive to the excitatory actions of FMRFamide in the 10(-9) to 10(-5) mol l-1 range. Preparations were insensitive to GAPFLRFamide, but SCP-B was modestly excitatory (threshold 10(-7) mol l-1). 5. Preparations were not significantly affected by adenosine, ATP, and guanosine, but GTP was strongly excitatory at 10(-7) mol l-1. 6. 5HT and FMRFamide responses were additive. Preparations responded strongly to the adenylate cyclase activator forskolin and dibutyryl cAMP enhanced spontaneous contractions and 5HT responses, suggesting that the 5HT receptor may operate via a cAMP secondary mechanism. 7. The IP3 inhibitor lithium (10 mmol l-1), caused slight inhibition of FMRFamide responses, suggesting that the receptor to this peptide may operate via IP3 as a second messenger. 8. Neuromodulation in this preparation would appear to involve ACh as inhibitor, 5HT and FMRFamide as upregulators, with no clear roles for FMRFamide-related peptides and GTP.
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PMID:Modulatory mechanisms in the isolated internally perfused ventricle of the whelk Busycon canaliculatum. 884 83

Cardiopulmonary bypass (CPB) is often followed by pulmonary hypertension, but the effects of extracorporeal circulation on vascular reactivity remain largely unknown. In this study, the influence of total CPB (t-CPB) on beta-adrenergic and cholinergic receptor-mediated pulmonary microvascular responses was examined. Sheep were placed on t-CPB without ventilation. After 90 min, sheep were separated from t-CPB and the lungs were perfused normally for 60 min. Pulmonary artery infusion of acetylcholine (muscarinic cholinergic agonist, ACh) increased pulmonary vascular resistance significantly more and isoproterenol (beta-adrenergic agonist, Iso) decreased pulmonary vascular resistance less after than before t-CPB. The response to sodium nitroprusside (SNP, guanylate cyclase activator) was similar before and after t-CPB. Relaxations (in vitro) of isolated pressurized (20 mmHg) microvessels to Iso and ACh were markedly reduced after t-CPB. Treatment with NPC-15669 (N-[9H-(2,7,-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine) did not affect these changes in vessel reactivity, although leukocyte sequestration in the lungs was reduced with the drug. The in vitro response to forskolin (adenylate cyclase activator) and SNP was similar before and after t-CPB. Complement-activated serum caused microvessels to contract in response to ACh, but it had no effect on Iso, forskolin, or SNP responses, suggesting that activation of the alternate complement pathway causes a selective reduction in endothelium-dependent relaxation. We conclude that t-CPB impairs cholinergic and beta-adrenergic pulmonary vascular responses due to effects at the level of the transmembrane receptor or coupling to the second messenger systems.
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PMID:Altered beta-adrenergic and cholinergic pulmonary vascular responses after total cardiopulmonary bypass. 884 66

We observed the movement of insulin granules in living transformed hamster pancreatic beta-cells (HIT T15) with a light microscope, where secretory granules are moving in the cytoplasmic space. Velocity of the typical granule movement was approximately 1.5 microns/sec. A stimulatory concentration of glucose activated the movement of the secretory granules. Forskolin, an activator of adenylate cyclase, increased the movement, resulting in changes in intracellular localization of the granules. Acetylcholine also activated the granule movement, whereas high K+ and tolbutamide, which cause Ca2+ influx through the voltage-dependent Ca2+ channel, had only little effect. The movement was abolished by BAPTA, the intracellular Ca2+-chelator. Activation of protein kinase C by 12-O-tetradecanoyl-phorbol 13-acetate failed to affect this movement. The motile events were inhibited by the calmodulin antagonist, W-7, and dramatically increased by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. These results suggest protein phosphorylation by Ca2+/calmodulin- and cAMP-dependent protein kinases play a positive role in the control of the insulin granule movements, which results in potentiation of insulin release from the pancreatic beta-cell.
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PMID:Ca2+/calmodulin and cyclic 3,5' adenosine monophosphate control movement of secretory granules through protein phosphorylation/dephosphorylation in the pancreatic beta-cell. 889 28


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