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)

Ventricular myocytes dissociated from adult rat heart and cultured chick embryo ventricular cells were utilized to examine mechanisms by which neurotransmitters, hormones, and ontogeny modulate expression and function of beta-adrenergic receptors and L-type calcium channels. Either freshly dissociated cells or cultured cells were studied by an optical-video system to characterize contractility and, in some instances, by a microspectrofluorimeter to determine [Ca2+]i as reported by fura 2. Ligand binding studies in intact cells and membranes were conducted with receptor and ion channel antagonists and agonists. Exposure of intact cells to isoproterenol produced contractile de-sensitization, loss of high affinity receptors from the sarcolemma and closely coupled decline in hormone-sensitive adenylate cyclase activity. De-sensitization was by a microfilament-dependent process. Down-regulation depended upon microtubular function. During development of the chick heart, there was an increase in number of dihydropyridine binding sites, taken as a measure of number of L-type calcium channels, at a time when sensitivity to [Ca2+]o and to Bay k 8644 declined. Thyroid hormone was capable of up-regulating L-type calcium channels. Prolonged exposure to a beta-adrenergic agonist produced coordinate down-regulation of beta-receptors and calcium channels. Down-regulation was a cAMP-dependent process. Thus, the beta-adrenergic receptor and a distal component of the effector-response coupling system, the L-type calcium channel, can be regulated independently and in concert by physiologically and pathophysiologically important mechanisms.
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PMID:Myocyte response to stimulation of receptors and ion channels. 198 74

L-type calcium channel activity of some excitable cells is markedly enhanced by beta-adrenergic agents. The enzymatic cascade underlying this important modulatory effect has been studied with patch-clamp techniques in single dialyzed ventricular cells from guinea pig heart. The steps between the binding of agonist to the beta-receptor and the increase in calcium influx can be summarized as follows: Agonist binding to beta-receptor greater than adenylate cyclase increases greater than cAMP increases greater than cA-kinase increases greater than protein phosphorylation greater than altered calcium channel properties greater than ICa increases A basal phosphorylation reaction seems not to be a prerequisite for calcium channel function. By combining molecular and functional approaches, the purified dihydropyridine-receptor complex from rabbit skeletal muscle transverse-tubules can be reconstituted in phospholipid bilayer membranes to form a functional 20-pS calcium channel that retains the principal regulatory, biochemical, and pharmacologic properties of membrane-bound L-type calcium channels.
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PMID:Modulation of calcium channel function by phosphorylation in guinea pig ventricular cells and phospholipid bilayer membranes. 244 71

beta-Adrenergic stimulation of ventricular heart cells results in the enhancement of two important ion currents that regulate the plateau phase of the action potential: the delayed rectifier potassium channel current (IK) and L-type calcium channel current (ICa). The temperature dependence of beta-adrenergic modulation of these two currents was examined in patch-clamped guinea pig ventricular myocytes at various steps in the beta-receptor/cyclic AMP-dependent protein kinase pathway. External applications of isoproterenol and forskolin were used to activate the beta-receptor and the enzyme adenylate cyclase, respectively. Internal dialysis of cyclic 3',5'-adenosine monophosphate (cAMP) or the catalytic subunit of cAMP-dependent protein kinase (CS), as well as the external addition of 8-chlorphenylthio cAMP (CPT-cAMP) was applied to increase intracellular levels of cAMP and CS. Isoproterenol-mediated increases in IK, but not ICa, were found to be very temperature dependent over the range of 20-37 degrees C. At room temperature (20-22 degrees C) isoproterenol produced a large (threefold) enhancement of ICa but had no effect on IK. In contrast, at warmer temperatures (30-37 degrees C) both currents increased in the presence of this agonist and the kinetics of IK were slowed at -30 mV. A similar temperature sensitivity also existed after exposure to forskolin, CPT-cAMP, cAMP, and CS, suggesting that this temperature sensitivity of IK may arise at the channel protein level. Modulation of IK during each of these interventions was accompanied by a slowing in IK kinetics. Thus, regulation of cardiac potassium channels but not calcium channels involves a temperature-dependent step that occurs after activation of the catalytic subunit of cAMP-dependent protein kinase.
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PMID:Beta-adrenergic modulation of cardiac ion channels. Differential temperature sensitivity of potassium and calcium currents. 247 62

Calcium antagonists blunt the constrictor effects of vasoconstrictor agents. Differences in the sensitivity of several vasoconstrictors to the constrictor effect of calcium antagonists were quantified in experiments on rats and rabbits. In rats, the dose-response curves for pressor effects to angiotensin II were shifted in parallel to the right after treatment with isradipine, but not with prazosin and dihydralazine, suggesting that the antivasoconstrictor effect of isradipine was of a specific type. Blood pressure increases elicited by angiotension II or norepinephrine (alone, or with propranolol or propranolol plus prazosin) were also measured in rabbits and, again, isradipine caused parallel shifts of the dose-response curves. Both agonists thus appear to stimulate calcium entry, at least in resistance vessels, and via the same pathway, the L-type calcium channel. However, the angiotension II pressor effects were more sensitive to isradipine than those of norepinephrine in the presence of propranolol, and even more so in the presence of propranolol plus prazosin. These results suggest subtle and as yet unexplained differences, possible related to the activity of the adenylate cyclase system, in the chain of events leading to activation of the L-channels in vivo.
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PMID:Antivasoconstrictor effects of isradipine. A quantitative approach in anesthetized rats and conscious rabbits. 252 55

Urinary calcium excretion is regulated homeostatically. Regulation is achieved, in part, by the action of parathyroid hormone on Ca2+ absorption in the distal nephron. Parathyroid hormone increases Ca2+ absorption in the cortical portion of the thick ascending limb of Henle's loop in all species studied, in the murine distal convoluted tubule, and in the rabbit connecting tubule. All of these sites contain parathyroid hormone-stimulated adenylate cyclase. Both cellular and paracellular pathways of Ca2+ absorption are regulated by parathyroid hormone in the cortical portion of the thick ascending limb of Henle's loop. In both distal convoluted and connecting tubule cells, parathyroid hormone regulates transcellular Ca2+ absorption by controlling the insertion and open probability of luminal plasmalemmal Ca2+ ion channels. These channels are stimulated and inhibited by L-type calcium channel agonists and antagonists, respectively, but differ from similar channels in excitable cells in that membrane depolarization does not activate them. Parathyroid hormone also increases the driving force for diffusional Ca2+ ion entry from the luminal fluid into the cytosol by increasing the intracellular negative electrical potential (at least in murine distal convoluted tubule cells) by increasing the chloride ion conductance of the basolateral cell membrane. The effects of parathyroid hormone on the other components of cellular Ca2+ transport, via both protein kinases A and C and their interactions, remain to be examined.
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PMID:Parathyroid hormone action in calcium transport in the distal nephron. 774 58

Pharmacological studies on pirenzepine (PZ), 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) and AFDX-116 antagonism of carbachol (CCh)-induced contraction, inositol trisphosphate (IP3) production and cAMP formation revealed the involvement of M3 receptors in these responses. The PA2 values for PZ and 4-DAMP antagonism to CCh-induced contraction were 7.1 and 9.0, respectively, and AFDX-116 had no effect on these responses. Further, 4-DAMP was a much more potent inhibitor than PZ of CCh-stimulation of IP3 production and cAMP formation. Both L-type calcium channel blockers, which inhibit Ca2+ influx, and BAPTA, an intracellular calcium chelator, inhibited these biochemical and pharmacological responses due to CCh. It is concluded that both intracellular and extracellular Ca2+ mobilization are involved in muscarinic stimulation of cAMP production, and that M3 receptors are coupled to the activation of both phospholipase C and adenylate cyclase in this tissue. The data presented here are consistent with previous work that stimulation of muscarinic receptors in dog iris sphincter with CCh (> 5 microM) increases intracellular cAMP levels.
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PMID:M3 muscarinic receptors mediate an increase in both inositol trisphosphate production and cyclic AMP formation in dog iris sphincter smooth muscle. 820 21

We investigated age-related changes in the binding sites of muscarinic acetylcholine, forskolin, adenosine 3',5'-cyclic monophosphate (cAMP), and of a voltage-dependent L-type calcium channel blocker in the gerbil brain using receptor autoradiography. [3H]Quinuclidinyl benzilate (QNB), [3H]forskolin, [3H]cAMP, and [3H]PN200-110 were used to label muscarinic receptors, adenylate cyclase, cAMP-dependent protein kinase, and L-type calcium channels, respectively. In middle-aged animals (16-month-old gerbils), [3H]QNB, [3H]PN200-110, [3H]forskolin, and [3H]cAMP binding sites were elevated in the hippocampal region compared with that of young gerbils (4 weeks old). Further, a significant elevation in [3H]forskolin binding was seen in the nucleus accumbens. In contrast, [3H]QNB, [3H]PN200-110, and [3H]forskolin binding sites were reduced in the cerebellum, neocortex and thalamus, and hypothalamus in middle-aged animals, respectively. [3H]cAMP binding was not altered in other regions except for an elevation in the hippocampus. Thus, the age-related alterations in receptor binding may proceed by different mechanisms in various brain regions. Chronic vinconate treatment partly modulated the age-related alterations in [3H]QNB, [3H]forskolin, and [3H]cAMP binding in the hippocampus, but not that of [3H]PN200-110. Vinconate also regulated the age-related changes in [3H]forskolin binding in the nucleus accumbens. These results indicate that the age-related alterations in the binding sites of muscarinic acetylcholine, forskolin, cAMP, and L-type calcium channel blocker occur in particular in the hippocampus. Further, they suggest that a novel vinca alkaloid derivative, vinconate, can partly modulate age-related changes in these binding sites.
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PMID:Effect of vinconate against regional age-related changes in the gerbil brain. 838 45

The effect of intrathecal injection of dynorphin A (1-17) on second messenger systems of spinal cord relative to behavioral change in rats was studied. Dynorphin A (1-17) 5, 10 (20 nmol) caused dose-dependent flaccid paralysis of hindlimbs. Dynorphin A (1-17) 10, 20 nmol dose-dependently decreased spinal adenylate cyclase (AC) activity, cyclic AMP production, calmodulin (CaM) level and cyclic-nucleotide phosphodiesterase (PDE) activity 10 min after intrathecal injection. They recovered to a varying extent two hours later. Pretreatment with selective kappa-opioid receptor antagonist nor-BNI 30 nmol 10 min before dynorphin A (1-17) markedly antagonized the effects of dynorphin A (1-17) at 20 nmol on hindlimb paralysis and inhibition of intracellular second messengers. The L-type calcium channel blocker verapamil (100 nmol) also played a role in blocking dynorphin neurotoxicity. The NMDA receptor antagonist APV could partially or completely block dynorphin inhibition of CaM level and PDE activity without affecting paralysis and decrease of AC-cAMP level induced by dynorphin A (1-17) 10 min after intrathecal injection.
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PMID:Effects of dynorphin A (1-17) on motor function and spinal intracellular messenger systems in rat. 938 10

We tested the hypothesis that part of the decreased function and metabolism caused by cyclic guanosine monophosphate (GMP) in beating cardiac myocytes is related to inhibition of L-type calcium channels. The steady state oxygen consumption (VO2) of a suspension of ventricular myocytes isolated from hearts of New Zealand white rabbits was measured using oxygen electrodes. Cellular cyclic GMP levels were determined by radioimmunoassay. Cell shortening was measured with a video edge detector. The VO2 was obtained after: (1) adding sodium nitroprusside (NP 10(-8),(-6),(-4) M), (2) pretreatment by BAY K8644 10(-5) M (BAY, L-type calcium channel activator), nifedipine 10(-4) M (NF, L-type calcium channel blocker) or forskolin 10(-7) M (FK, adenylate cyclase activator), then adding NP 10(-8),(-6),(-4) M, (3) pretreatment with both FK 10(-7) M and NF 10(-4) M and subsequently adding NP 10(-8),(-6),(-4) M. NP 10(-4) M decreased VO2 from 707 +/- 34 to 410 +/- 13 (nl O2/min per 10(5) myocytes), decreased the percentage of shortening (Pcs) from 5.7 +/- 0.6 to 3.7 +/- 0.5 and the rate of shortening (Rs) from 65.5 +/- 4.5 (microns/s) to 46.2 +/- 5.5. NP 10(-4) M also increased cyclic GMP from 264 +/- 70 (fmol/10(5) myocytes) to 760 +/- 283. Both BAY and FK increased VO2, Pcs and Rs without changing cyclic GMP. NF decreased Pcs, Rs and VO2. Similar metabolic and functional effects of NP were observed with pretreatment with these agents separately, compared to NP alone, and the elevation of cyclic GMP level was not different from the control group. With FK alone, NP 10(-4) M decreased VO2 by 51%, Pcs by 44% and Rs by 39%. In the presence of both FK and NF, the negative effects of NP were diminished significantly. NP 10(-4) M decreased VO2 by 37%, Pcs by 25% and Rs 20%. Thus, in beating cardiac myocytes, the negative metabolic and functional effects of cyclic GMP were related to inhibition on L-type calcium channels only when adenylate cyclase was stimulated.
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PMID:Relationship between decreased function and O2 consumption caused by cyclic GMP in cardiac myocytes and L-type calcium channels. 982 Aug 98

Nitric oxide (NO) is continuously produced in the lung and is present in exhaled air. We examined the effect of beta-adrenoceptor stimulation on the production of pulmonary NO in rabbits. Exhaled NO was measured by chemiluminescence in anaesthetized and mechanically ventilated rabbits and in buffer-perfused rabbit lungs. Intravenous infusions of adrenaline (0.1-10 microg kg(-1) min(-1)) elicited dose-dependent increases in exhaled NO. The increases in exhaled NO comprised an initial peak followed by a lower plateau level. The increase in exhaled NO was inhibited by propranolol (1 mg kg(-1)) but not by phentolamine (1 mg kg(-1)). Prenalterol, a beta1-adrenoceptor agonist, and terbutaline, a beta2-adrenoceptor agonist, also caused dose-dependent increases in exhaled NO. However, prenalterol was >100 times more potent than terbutaline. Infusions of forskolin (0.01-0.03 micromol kg(-1) min(-1)), an adenylate cyclase stimulator, elicited dose-dependent decreases in blood pressure and concomitant increases in heart rate but caused no alterations in exhaled NO. Nimodipine, a L-type calcium channel blocker, antagonized the increases in exhaled NO in response to prenalterol infusions. The increases in exhaled NO in response to adrenaline and prenalterol were also present in blood-free, buffer perfused lungs during constant-flow conditions. These results demonstrate that pulmonary nitric oxide production can be enhanced by beta-adrenoceptor stimulation. Furthermore, the results indicate that the beta-adrenergic stimulation of pulmonary NO production is not critically dependent on cyclic AMP formation but may require intact calcium-channels.
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PMID:Beta-adrenoceptor agonist stimulation of pulmonary nitric oxide production in the rabbit. 1018 98


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