Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 from slices of rabbit hippocampus was elicited by electrical field stimulation (360 pulses/3 Hz). Both forskolin, commonly used as a specific activator of adenylate cyclase, as well as 1,9-dideoxy-forskolin, which fails to activate adenylate cyclase, increased the evoked transmitter release in an almost identical manner. In addition, the phosphodiesterase inhibitor, rolipram, and the membrane-permeable analogue of cAMP, 8-Br-cAMP, did not influence acetylcholine release. These data show that forskolin is not specific to adenylate cyclase and that the increase in acetylcholine release in the rabbit hippocampus occurs through a mechanism other than activation of adenylate cyclase.
 ...
PMID:Forskolin modulates acetylcholine release in the hippocampus independently of adenylate cyclase activation. 238 34

The effects of muscarinic cholinergic stimulation on beta-adrenergic induced increases in phospholamban phosphorylation and Ca2+ transport were studied in intact myocardium. Isolated guinea pig ventricles were perfused via the coronary arteries with 32Pi, after which membrane vesicles were isolated from individual hearts. Isoproterenol produced reversible increases in 32P incorporation into phospholamban. Associated with the increases in 32P incorporation were increases in the initial rate of phosphate-facilitated Ca2+ uptake measured in aliquots of the same membrane vesicles isolated from the perfused hearts. The increases in 32P incorporation and calcium transport were significantly attenuated by the simultaneous administration of acetylcholine. Acetylcholine also attenuated increases in phospholamban phosphorylation and Ca2+ uptake produced by the phosphodiesterase inhibitor isobutylmethylxanthine and forskolin. The contractile effects of all agents which increased cAMP levels (increased contractility and a reduction in the t1/2 of relaxation) were also attenuated by acetylcholine. The inhibitory effects of acetylcholine were associated with attenuation of the increases in cAMP levels produced by isoproterenol and isobutylmethylxanthine but not by forskolin. Acetylcholine also increased the rate of reversal of the functional and biochemical effects of isoproterenol by propranolol without affecting cAMP levels. These results suggest that cholinergic agonists inhibit the functional effects of beta-adrenergic stimulation in part by inhibition of phospholamban phosphorylation. This inhibition may be mediated by two potential mechanisms: inhibition of beta-adrenergic activation of adenylate cyclase and stimulation of dephosphorylation.
 ...
PMID:Muscarinic cholinergic inhibition of beta-adrenergic stimulation of phospholamban phosphorylation and Ca2+ transport in guinea pig ventricles. 241 74

The K+ current response to bath-applied adenosine has been studied on follicle-enclosed full grown oocytes from Xenopus laevis, using the two electrodes voltage-clamp technique. The response to adenosine was mimicked by forskolin, an activator of adenylate cyclase. Forskolin applied at low concentration potentiated the response to adenosine. At low concentration, isoprenaline, a beta-adrenergic agonist known to induce a potassium current via a rise of adenosine 3',5'-phosphate (cyclic AMP) into the oocyte, potentiated the response to adenosine. Progesterone (10(-5) M) reversibly induced a slight decrease (-24%) of the response to adenosine. The calcium ionophore A23187 applied in normal external medium reduced the response to adenosine (about -70%). Intracellular injection of EGTA induced an increase (+64%) of the peak response to adenosine. Acetylcholine (0.5-10 microM) inhibited the response to 3-10 microM adenosine by 44-91%. This inhibition was suppressed by atropine and was seen even on cells which did not show any current in response to acetylcholine application. The inhibition by ACh of the sensitivity to adenosine was long lasting (more than 1 h after the wash-out of ACh). A long term inhibition (-28 to -90%) also occurred when ACh was applied alone and washed before adenosine application. It is concluded that in Xenopus oocyte: increased cyclic AMP synthesis mediates the potassium response to adenosine; intracellular calcium ion concentration modulates this response; muscarinic stimulation induces a long-lasting inhibition of the sensitivity to adenosine.
 ...
PMID:Cyclic adenosine monophosphate, calcium, acetylcholine and the current induced by adenosine in the Xenopus oocyte. 242 7

The slow inward Ca2+ current, ICa, is fundamental in the initiation of cardiac contraction and neurohormonal regulation of cardiac function. It is increased by beta-adrenergic agonists, which stimulate synthesis of cyclic AMP (cAMP) and cAMP-dependent phosphorylation. The neurotransmitter acetylcholine reduces ICa by an unknown mechanism. There is strong evidence that acetylcholine reduces ICa by decreasing adenylate cyclase activity, but cGMP has also been implicated as ACh stimulates cGMP accumulation and activates cGMP-dependent protein kinase. Application of cGMP decreases contractile force, decreases Ca flux, shortens the duration of action potentials and inhibits Ca-dependent action potentials. Other studies, however, have concluded that cGMP levels do not correlate with contractile force and that cGMP has no effect on ICa. We have therefore examined the effects of intracellular perfusion of cGMP on ICa using isolated, voltage-clamped cells from frog ventricle. We find that cGMP has negligible effects on basal ICa, but greatly decreases the ICa that had been elevated by beta-adrenergic agonists or by intracellular perfusion with cAMP. The decrease of ICa is mediated by cAMP hydrolysis via a cGMP-stimulated cyclic nucleotide phosphodiesterase.
 ...
PMID:Opposite effects of cyclic GMP and cyclic AMP on Ca2+ current in single heart cells. 242 89

Intracellular recordings from primary mechanosensory neurones (dorsal cells) in the lamprey spinal cord were used to test the membrane effects of a variety of putative neuromodulatory agents. gamma-Aminobutyric acid (GABA) produced a dose-dependent increase in the duration of mixed Na-Ca or pure Ca action potentials in these cells. L-Glutamate and glycine produced minimal broadening of Ca action potentials. Acetylcholine, noradrenaline, serotonin, met-enkephalin, D-glutamate and dopamine had no effect. The pharmacology of GABA's action appeared to be complex. While the GABAA receptor antagonists, bicuculline, picrotoxin and curare, did not block GABA's effect, both the GABAA receptor agonist, muscimol, and the GABAB-receptor agonist, baclofen, occasionally broadened Ca action potentials in these cells. GABA had no effect on the resting potential, passive current-voltage (I-V) characteristics and pure Na action potential of dorsal cells, ruling out an action on passive membrane channels, transmitter-activated channels, or on those voltage-dependent channels activated during the Na action potential. Thus, GABA affected dorsal cells only when a significant Ca current was evident. GABA appeared not to increase the conductance of the Ca channels since its action was accompanied by an increase in input resistance, suggesting an inhibition of Ca-dependent conductance that normally acts to repolarize the membrane during a Ca action potential. An inhibitory effect of GABA on a Ca-dependent Cl conductance was ruled out in experiments where the Cl gradient was altered by removal of extracellular Cl without affecting GABA-induced Ca action potential prolongation. Dorsal cells have a prominent Ca-dependent K conductance (gK(Ca], and it is this conductance that GABA may inhibit. Consistent with this was the observation that the hyperpolarizing after-potential that follows Ca action potentials in dorsal cells, which reflects gK(Ca) in these cells and whose duration is normally increased when the Ca action potential duration increases, was not prolonged when the Ca action potential was broadened by GABA. Further, the failure of GABA to prolong Ba action potentials was consistent with this proposed mechanism of action, since Ba apparently does not activate gK(Ca) in these cells. Forskolin, a specific adenylate cyclase activator, caused broadening of Ca action potentials in lamprey dorsal cells comparable in magnitude to that of GABA. Thus, an increase in intracellular cyclic AMP is a candidate for the intracellular mediator of GABA's effect on these cells.
 ...
PMID:Prolongation of calcium action potentials by gamma-aminobutyric acid in primary sensory neurones of lamprey. 243 26

The intracellular mechanisms by which cardiac Ca current (ICa) and the delayed outward K current (IK) are modulated during beta-adrenergic or muscarinic stimulation were investigated at the level of both single-channel and whole-cell currents in single ventricular myocytes of guinea-pigs. Superfusion of cells with beta-adrenergic agonist increased the amplitude of whole-cell ICa in a dose-dependent manner. In the single-channel recording, neither the amplitude of elementary current nor the total number of active channels was affected but the number of blank records was markedly reduced resulting in a larger amplitude of the ensemble average current. Intracellular dialysis of cells with cyclic AMP (cAMP) or the catalytic (C) subunit of cAMP-dependent protein kinase (cAMP-PK) produced a dose-dependent increase in the amplitude of ICa and IK. A non-hydrolysable ATP analogue, AMP-PNP, reduced whereas ATP gamma S enhanced the effects of beta-agonist on ICa and IK, suggesting an involvement of protein phosphorylation during the enhancement of these currents. The regulatory subunit of cAMP-PK, the heat-stable protein-kinase inhibitor (PKI) and type-1 protein phosphatase antagonized the beta-adrenergic enhancement of ICa and IK, but did not eliminate ICa. Acetylcholine (ACh) reduced the amplitude of ICa when ICa was enhanced by either beta-adrenergic agonist, forskolin or 3-isobutyl-1-methyl-xanthine but did ACh not when ICa was enhanced by intracellular dialysis with cAMP or C subunit, suggesting that muscarinic inhibition occurs at the level of adenylate cyclase. Non-hydrolysable GTP analogue, GMP-PNP, uncoupled both beta-adrenergic and muscarinic modulation of ICa. Pertussis toxin selectively eliminated the effect of ACh on ICa. Based on these results, we concluded that the activities of the Ca channel and the delayed outward K channel are controlled by the action of neurotransmitters, which are mediated by GTP-binding proteins and cAMP-dependent protein phosphorylation. It is suggested that phosphorylation of 'Ca-channel-related protein' leads to an increased open probability without changing the total number of channels or the elementary current amplitude.
 ...
PMID:Intracellular control of calcium and potassium currents in cardiac cells. 243 80

The effect of extracellular and intracellular application of forskolin on the voltage-sensitive calcium current, ICa, was studied in myocytes isolated from frog ventricle. Myocytes were isolated by enzymatic dissociation, and ICa was measured using the whole-cell configuration of the patch clamp technique modified to permit intracellular perfusion of various substances. Intracellular perfusion with forskolin (0.1 to 10 microM) had a negligible effect on ICa: ICa was increased 15 +/- 13% (mean +/- SE; N = 5). In contrast, superfusion of the cell with forskolin increased ICa significantly. The EC50 for the forskolin effect was 0.4 microM. A maximal 4.5-fold increase in ICa occurred with 3 microM forskolin. This is somewhat less than the maximal response to isoprenaline seen in this same series of experiments. The effects of forskolin, isoprenaline, and intracellular cAMP were not additive. In contrast, the effects of isoprenaline or intracellular cAMP and calcium channel agonists, such as Sandoz (+)202-791, were additive. This supports the hypothesis that the positive inotropic effects of forskolin are at least partly mediated by an increase in intracellular cAMP and a stimulation of ICa. The effects of forskolin were antagonized by acetylcholine (1 microM) or intracellular perfusion with cGMP. Acetylcholine on the average decreased forskolin-stimulated ICa 57 +/- 11% (N = 17). The relevance of these results to the suggestion that acetylcholine acts by mechanisms other than inhibition of adenylate cyclase is discussed.
 ...
PMID:Effect of forskolin and acetylcholine on calcium current in single isolated cardiac myocytes. 244 14

1. Secretion of [3H]acetylcholine was studied in the guinea-pig ileum longitudinal muscle-myenteric plexus preparation. The transmitter stores of the cholinergic nerves were labelled by pre-incubation with [3H]choline. The preparation was mounted in an organ bath and superfused with Tyrode solution containing hemicholinium-3 and eserine. [3H]Acetylcholine secretion was evoked by electrical stimulation (0.5 Hz, 150 shocks). 2. 8-Bromo cyclic AMP, the adenylate cyclase activator forskolin, and the cyclic nucleotide phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine enhanced the [3H]acetylcholine secretion in a concentration-dependent manner. The values of 'maximal enhancement' calculated were similar, viz. 200-300% of control. 3. 8-Bromo cyclic GMP reduced the [3H]acetylcholine secretion. 4. The 'maximal enhancement' of 3-isobutyl-1-methylxanthine was not altered by the presence of forskolin (25 mumol/l) suggesting a common mechanism of action, i.e. elevation of endogenous cyclic AMP levels. 5. The muscarinic acetylcholine receptor antagonist atropine enhanced the [3H]acetylcholine secretion with a 'maximal enhancement' of 506% of control. Presence of neither forskolin (25 mumol/l) nor 3-isobutyl-1-methylxanthine (5 mmol/l) altered the 'maximal enhancement' for atropine. 6. In contrast, atropine (1 mumol/l) and 4-aminopyridine (0.5 mmol/l) additively enhanced the [3H]acetylcholine secretion. 7. The results suggest that neuronal cyclic AMP may be involved in muscarinic acetylcholine receptor-mediated control of [3H]acetylcholine secretion in guinea-pig ileum myenteric plexus.
 ...
PMID:Interaction of forskolin with the effect of atropine on [3H]acetylcholine secretion in guinea-pig ileum myenteric plexus. 245 81

Incubating skeletal muscle fibers with forskolin, an activator of adenylate cyclase, increases the rate at which nicotinic acetylcholine receptors (AChRs) desensitize when exposed to ACh. Several reports indicate that this is due to the phosphorylation of AChRs by cAMP-dependent protein kinase, but other studies suggest that forskolin interacts with AChRs directly and that second-messenger systems are not required. To help clarify this issue, we studied the effects of forskolin and several other drugs on AChR function in embryonic rat myotubes. AChR function was studied by recording ACh-induced membrane depolarizations and ACh-induced single-channel currents. Our results indicate that forskolin at low concentrations enhances AChR desensitization through the action of a second messenger, most likely cAMP. An analog of forskolin that is much less effective in activating adenylate cyclase (1,9-dideoxyforskolin) is also much less potent in enhancing desensitization. Forskolin at low concentrations does not alter single-channel conductance or mean channel open time. However, when used at concentrations above 20 microM, forskolin may also exert direct drug effects on AChRs.
 ...
PMID:Desensitization of acetylcholine receptors in rat myotubes is enhanced by agents that elevate intracellular cAMP. 245 25

The cholinergic antagonism of beta-adrenergic stimulation was examined by measuring adenylate cyclase activity and calcium-mediated action potentials in isolated ventricular cardiomyocytes of adult rabbits. The beta-adrenoceptor agonist isoproterenol and the direct adenylate cyclase activator forskolin increased adenylate cyclase activity in homogenates of the myocytes. The cholinergic agonist carbachol (10 nM-100 microM) inhibited in a concentration dependent manner basal, isoproterenol-stimulated and forskolin-stimulated adenylate cyclase activity. The carbachol effect on basal adenylate cyclase activity was antagonized by atropine (10 microM). In parallel experiments using intact cardiomyocytes, calcium action potentials were elicited by intracellular depolarizing current pulses in partially depolarized preparations. These action potentials were prolonged by isoproterenol, forskolin and dibutyryl cyclic AMP. Acetylcholine reversibly inhibited the prolongation of the action potential induced by isoproterenol and forskolin but not dibutyryl cyclic AMP. These results suggest that cholinergic agonists modulate the increase in the calcium current elicited by isoproterenol and forskolin in isolated ventricular cardiomyocytes by inhibiting adenylate cyclase activity.
 ...
PMID:Cholinergic antagonism of beta-adrenergic stimulated action potentials and adenylate cyclase activity in rabbit ventricular cardiomyocytes. 246 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>