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)

We examined a variety of factors that might modulate the initiation of neurite outgrowth in an attempt to identify means by which its initiation might be accelerated. We examined this initiation from an identified molluscan neuron, Helisoma trivolvis buccal neuron B5 after axotomy, and determined whether the site of injury, temperature, ion channel blockers, pH, the second messenger cAMP, and protein synthesis affect the initiation of neurite outgrowth. Neurite outgrowth was assayed from axotomized neurons by filling the neurons intracellularly with Lucifer Yellow and examining the percentage of axons that extended (sprouted) new process after 9 or 24 h in organ culture. About one-third (31%) of axotomized neurons sprouted from the site of injury after 9 h (n = 22), and 88% (n = 20) sprouted after 24 h in saline at 22 degrees-24 degrees C when the injury was located 800 microns from the soma. Elevating the temperature to 32 degrees C or moving the lesion site to 400 or 1500 microns from the soma did not significantly alter the incidence of sprouting. Blocking sodium channels with tetrodotoxin [TTX (2 x 10(-5) M)] did not significantly reduce the incidence of sprouting, whereas the sodium channel agonist, veratridine (10(-5) M) did. The calcium channel blocker lanthanum (10(-6)-10(-4) M), stimulated neurite outgrowth; however, the organic calcium channel blocker verapamil (10(-3)-10(-5) M), and the calcium ionophore A23187 (10(-5) M), had no effect on sprouting. Exposure of neurons to the potassium channel blocker tetraethylammonium [TEA (20 mM)], elevation of intracellular pH with NH4Cl (5 mM), or treatment with the adenylate cyclase activator forskolin (10(-5) M) reduced the incidence of sprouting, whereas dideoxy-forskolin (10(-5) M) had no effect. Inhibition of protein synthesis with anisomycin (2 x 10(-4) to 2 x 10(-6) M) did not significantly suppress sprouting 24 h after axotomy. Both D and L isomers of glutamate (300 microM) stimulated sprouting. The present results suggest that the initiation of sprouting is regulated locally at or near the site of injury, and that blocking specific ion channels may either inhibit or enhance the initiation of neurite outgrowth.
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PMID:Modulation of sprouting in organ culture after axotomy of an identified molluscan neuron. 132 84

Amiloride, a potent blocker of the sodium channel in airway epithelium, has been administered by aerosol as a therapeutic agent for cystic fibrosis. Because amiloride in high concentration has been reported to interfere with cell functions, including adrenergic responses, we tested the ability of amiloride to inhibit beta-adrenergic responses in human tracheal epithelial cells. Amiloride (10(-4) M), applied from the basolateral surface of a cell monolayer, inhibited the changes in transepithelial potential and short circuit current to isoproterenol (10(-6) M). The stimulation of cyclic adenosine monophosphate (cAMP) synthesis by isoproterenol was inhibited in dose-dependent fashion by amiloride (P = 0.007 by multivariate ANOVA with multiple samples correction). Amiloride did not affect baseline transepithelial potential, short circuit current, basal cAMP levels, cAMP response to prostaglandin E2, or basal adenylate cyclase activity measured directly in membrane preparations. Therefore, it is unlikely that amiloride exerts a nonspecific toxic effect on adenylate cyclase, receptor-cyclase coupling, or substrate or cofactor supply. The binding of [125I]iodocyanopindolol (ICYP), a beta-adrenergic receptor antagonist, to membranes from human tracheal epithelial cells could be displaced by amiloride with IC50 = 410 microM; displacement was 70% at 10(-3) M amiloride. These data are most consistent with the hypothesis that amiloride inhibits beta-adrenergic responses in airway epithelial cells by occupying beta-adrenergic receptor sites. Therapeutic administration of amiloride should take into account its affinity for adrenergic receptors.
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PMID:Amiloride antagonizes beta-adrenergic stimulation of cAMP synthesis and Cl- secretion in human tracheal epithelial cells. 134 24

Cocaine can induce lethal cardiovascular events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic effects of cocaine remain largely to be determined. Cocaine has both sympathomimetic (inhibition of neuronal uptake of norepinephrine) and local anesthetic (Na+ channel blockade) properties. Neurotransmitters released from cardiac sympathetic nerves bind to both alpha- and beta-adrenergic receptors eliciting a cascade of intracellular responses. Stimulation of beta-adrenergic receptors activates adenylate cyclase, increasing cyclic AMP levels, whereas alpha-adrenergic receptor stimulation activates phospholipase C, increasing inositol trisphosphate. These second messengers, in turn, elicit increases in cystolic calcium. Elevations in cystolic calcium can provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potential generation and extrasystoles. Cocaine also acts as a local anesthetic by inhibiting sodium influx into cardiac cells, which impairs impulse conduction and creates an ideal substrate for reentrant circuits. Thus, the adrenergic and anesthetic properties of cocaine could act synergistically to elicit and maintain ventricular fibrillation. Adrenergic receptor activation would trigger the event whereas sodium channel blockade would create the reentrant substrate to perpetuate the malignant arrhythmias.
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PMID:Mechanisms responsible for the cardiotoxic effects of cocaine. 218 73

The present study demonstrates that 3,4-dihydroxyphenylethylamine (DA, dopamine) prevents neurotensin (NT) stimulation of both prolactin (PRL) release and calcium influx by interacting with specific receptors that are functionally linked to calcium channels. As shown by the studies with dispersed cells from rat anterior pituitary, the pharmacology of the control of PRL release and calcium influx, both induced by NT, was found to be typical of a DAergic process. This was demonstrated by the order of potency of agonists in inhibiting PRL release and calcium influx (DA greater than epinephrine greater than norepinephrine much greater than isoproterenol); by the high affinity of antagonists such as haloperidol and fluphenazine for this process; and by the high degree of stereoselectivity of sulpiride. Specific D2 receptor agonists, such as bromocriptine and lisuride, and the specific D2 receptor antagonist (-)-sulpiride were found to be highly potent on the DA receptors negatively coupled with calcium channels and PRL release. DA was found to lack the capacity to change the influx of calcium induced by either the sodium channel activator veratridine or high extracellular potassium levels, thus indicating a specific action of this amine on calcium channels sensitive to NT. In a range of concentrations that are effective in inhibiting either the calcium influx or the PRL release, both induced by NT, DA did not alter the cyclic AMP generating system. DA (from 1.0 nM to 50 nM) did not affect adenylate cyclase activity in rat pituitary gland homogenates and did not modify intracellular cyclic AMP levels in pituitary cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopaminergic inhibition of prolactin release and calcium influx induced by neurotensin in anterior pituitary is independent of cyclic AMP system. 243 58

The effect of 8-bromocyclic AMP (8-Br-cAMP) and phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, on cytosolic free calcium concentration ([Ca2+]i) in normal rat anterior pituitary cells was examined. [Ca2+]i was monitored directly by the fluorescent indicator fura-2. 8-Br-cAMP as well as PMA elevated [Ca2+]i in a concentration-dependent manner. Forskolin (10 mumol/l), which activates adenylate cyclase, and 1-oleoyl-2-acetyl-glycerol (10 mumol/l), another activator of protein kinase C, also increased [Ca2+]i. Both the 8-Br-cAMP (2 mmol/l)- and the PMA (100 nmol/l)-induced increase in [Ca2+]i was dependent on the presence of extracellular calcium and could be inhibited by the calcium channel blockers Mg2+ and nifedipine, but not by omega-conotoxin (100 nmol/l). The half-maximally inhibitory concentrations of Mg2+ and nifedipine were about 12 mmol/l and 160 nmol/l, respectively, for the [Ca2+]i response to 8-Br-cAMP (2 mmol/l), and were about 6 mmol/l and 400 nmol/l, respectively, for the PMA (100 nmol/l)-induced increase in [Ca2+]i. The sodium channel blocker tetrodotoxin (5 mumol/l) or PMA (100 nmol/l) on [Ca2+]i. After pretreatment for 3 min with PMA (100 nmol/l), the subsequent K+ (100 mmol/l)- or arachidonic acid (3 mumol/l)-induced increase in [Ca2+]i was decreased by about 50%. By contrast, pretreatment (3 min) with 8-Br-cAMP (2-10 mmol/l) markedly enhanced the subsequent [Ca2+]i response to K+ (100 mmol/l), and left the effect of arachidonic acid (3 mumol/l) on [Ca2+]i unimpaired.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:cAMP- and diacylglycerol-mediated pathways elevate cytosolic free calcium concentration via dihydropyridine-sensitive, omega-conotoxin-insensitive calcium channels in normal rat anterior pituitary cells. 254 3

The positive inotropic activity of the novel cardiotonic DPI 201-106 was investigated in rat and guinea pig isolated hearts. For comparative purposes, the adenylate cyclase stimulant forskolin and the sodium channel agonist veratridine were also evaluated in both species. DPI 201-106 and veratridine produced greater inotropic effects in rat hearts than in guinea pig hearts, whereas forskolin produced comparable effects. In both species the inotropic response to DPI 201-106 and veratridine, but not forskolin, was reversed by the sodium channel antagonist tetrodotoxin. These results confirm that the positive inotropic effect of DPI 201-106 is due to stimulation of the sodium channel and demonstrate for the first time that species differences exist in the inotropic response to this novel cardiotonic drug.
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PMID:Species differences in the positive inotropic response to DPI 201-106, a novel cardiotonic agent. 256 Jun 76

alpha 2-Adrenergic receptors (alpha 2-AR) are negatively coupled to adenylyl cyclase via the GTP-binding protein Gi. However, inhibition of adenylylcyclase does not account for many effector cell responses to alpha 2-AR agonists, suggesting that the receptor can couple to other signal transduction pathways. One potential pathway may be the stimulation of Na+/H+ exchange elicited by alpha 2-AR activation in renal proximal tubule cells, platelets, and the NG-10815 cell line. To determine whether the various receptor-effector coupling mechanisms operate in a tissue-specific manner, we studied the effect of alpha 2-AR activation on basal and stimulated Na+/H+ exchange in epithelial cells isolated from human colon (HT-29 adenocarcinoma cells). Na+/H+ exchange was measured by quantitation of intracellular hydrogen ion concentration (acetoxymethyl ester 2,7-biscarboxyethyl-5(6)carboxyfluorescein) and 22Na+ uptake. HT-29 cells expressed an amiloride-sensitive Na+/H+ exchanger that was activated by reduction of intracellular pH (pHi) to 6.0 but was quiescent at a physiological pHi. The rapid alkalinization observed after acid loading (0.57 +/- 0.07 pH units/min/10(4) cells) was dependent on external sodium and was blocked by amiloride (Ki approximately 2.1 microM). Although epinephrine and the selective alpha 2-AR agonists clonidine and UK-14304 inhibited forskolin-activated adenylylcyclase, these compounds did not alter basal Na+/H+ exchange. Stimulated Na+/H+ exchange was similarly unaffected by epinephrine. In contrast, stimulated Na+/H+ exchanger activity was completely inhibited by the selective alpha 2-agonists clonidine, UK-14304, and guanabenz. This inhibitory effect was not blocked by the alpha 2-AR antagonist rauwolscine, and it is likely due to a direct interaction with the exchanger molecule itself. Structure/activity studies indicated that the compounds inhibiting exchanger activity possess either an imidazoline or guanidinium moiety. Although these molecules bear structural similarity to amiloride, they did not inhibit the amiloride-sensitive epithelial sodium channel in toad urinary bladder, suggesting that these compounds may be useful as "amiloride-like" ligands selective for the Na+/H+ exchanger. These data indicate that in the HT-29 intestinal cell line, in contrast to observations in other tissues, alpha 2-adrenergic receptors are not coupled to the Na+/H+ exchanger, suggesting that the cell-signaling mechanisms utilized by the alpha 2-AR are tissue specific.
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PMID:Alpha 2-adrenergic receptors and the Na+/H+ exchanger in the intestinal epithelial cell line, HT-29. 257 Jul 77

Sodium transport has been measured in the isolated epithelium from colons of male Sprague-Dawley rats. Sodium transport in colons was induced by pretreating the animals with dexamethasone (6 mg kg-1) which caused the appearance of an amiloride-sensitive short circuit current within a few hours. Forskolin, a diterpene, which activates adenylate cyclase, was found to increase the cyclic adenosine monophosphate (cyclic AMP) content of rat colons and also to increase short circuit current at the same time. However, measurements of chloride and sodium fluxes across the epithelium indicated that forskolin activates chloride secretion but has no effect on sodium transport. In confirmation of (3) it was found that the amiloride-sensitive short circuit current was unchanged after the short circuit current had been increased by forskolin under a variety of conditions. The behaviour of the mammalian colon as indicated in (3) and (4) is unlike that of amphibian sodium transporting epithelia. It is shown that in toad urinary bladder forskolin increases amiloride-sensitive short circuit current. Procedures were investigated which might make sodium transport in the mammalian colon sensitive to cyclic AMP. Exposing the apical surface to sonicated suspensions of nucleated red cells (frog, toad and duck), followed by washing, gave preparations with amiloride-sensitive short circuit currents which were increased by forskolin or dibutyryl cyclic AMP. It would appear that the sodium channel in the mammalian colon, unlike that of amphibian tissues, has lost the ability to have its properties modified by cyclic AMP. Incubation of colons with sonicated suspensions of nucleated red cells apparently modifies the tissues such that sodium transport across the tissue becomes sensitive to the nucleotide.
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PMID:Conversion of sodium channels to a form sensitive to cyclic AMP by component(s) from red cells. 631 20

To evaluate the role of transmembrane ion flux on the acute response of luteal cells to LH, the effects of two drugs, ouabain and monensin, and changes in ion composition of the medium were examined. Ouabain, an inhibitor of the Na+ extrusion pump, and monensin, a selective Na+ ionophore, would be expected to increase the intracellular level of Na+. Both drugs produced a highly significant, dose-related and Na+-dependent inhibition of LH-stimulated cAMP accumulation and progesterone secretion. The IC50 values for ouabain and monensin for both responses to LH were about 50 and 0.1 microM, respectively, and inhibition of cAMP accumulation was competitive [inhibitory constant (Ki) = 20 and 0.06 microM, respectively]. Both drugs showed inhibition only in the intact cell, and no nonspecific cytotoxic effects were evident. No effect on the specific binding of gonadotropin or on LH-stimulated adenylate cyclase activity in membranes was seen, nor was inhibition reduced by coincubation of the cells with isobutyl methylxanthine, a cAMP phosphodiesterase inhibitor. Both drugs inhibited (Bu)2cAMP-stimulated progesterone accumulation. No effect of ouabain was seen on cholera toxin- or forskolin-stimulated cAMP accumulation, whereas monensin significantly inhibited this response to both agonists. Preincubation of cells with LH protected against inhibition of cAMP accumulation by ouabain and monensin. Removal of extracellular Na+ completely prevented inhibition by both drugs and slightly blunted the response to LH alone. However, reduction of extracellular Na+ from 128 to 32 mM, treatment of cells with tetrodotoxin (a sodium channel blocker), or increasing extracellular K+ from 5.4 to 66 mM had no effect on the stimulation of cAMP accumulation by LH. On the other hand, removal of extracellular Ca2+ completely blocked inhibition of LH-stimulated cAMP accumulation by ouabain or monensin. It is concluded that ouabain and monensin inhibit the acute stimulation of cAMP accumulation by LH probably as a result of an influx of Na+ into the luteal cell. The increase in intracellular Na+ does not appear to directly inhibit LH-sensitive adenylate cyclase activity, but induces a secondary influx of extracellular Ca2+ which inhibits activation of adenylate cyclase by LH at a site involved in coupling of the receptor to the enzyme. Luteal regression may be initiated by mechanisms similar to that caused by ouabain and monensin, because the characteristics of inhibition by these drugs is identical to that caused by prostaglandin F2 alpha, a physiological luteolysin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alteration of transmembrane sodium and potassium gradients inhibits the action of luteinizing hormone in the luteal cell. 632 32

Corticosteroid regulation of Na/K-ATPase is of key importance in the modulation of Na+ transport across renal tubular epithelia. In amphibian renal cells, aldosterone induction of Na/K-ATPase alpha 1 and beta 1 subunit gene transcription is mediated by an indirect mechanism dependent on the synthesis of a labile protein. In mammalian target cells, while both mineralo- and glucocorticoids increase the levels of Na/K-ATPase alpha 1 and beta 1 subunit mRNA and enzyme activity, they are diminished by glycyrrhetinic acid (GE), the active ingredient of licorice. To investigate the mechanisms underlying the regulation of mammalian renal Na/K-ATPase, levels of alpha 1 and beta 1 mRNA were measured in rat kidney epithelial (NRK-52E) cells treated with a range of concentrations of aldosterone, corticosterone and GE in the presence of a specific inhibitor of mRNA synthesis, dichlororibofuranosylbenzimidazole (DRB), an inhibitor of total RNA synthesis, actinomycin D (ActD), and the protein synthesis inhibitor cycloheximide (CHX). In addition, GE was co-incubated with the sodium channel antagonist benzamiloride (BZ). The increase in both alpha 1 and beta 1 mRNA levels following aldosterone and corticosterone was completely abolished by treatment with ActD and DRB, while CHX did not affect this response. Similarly, the GE-induced decrease in alpha 1 and beta 1 mRNA was also completely abolished by ActD and DRB, but not by CHX or by BZ. The half-lives of alpha 1 and beta 1 mRNA in these cells (means +/- S.E.M., n = 4), estimated from the rate of mRNA decay in the presence of DRB, were 6.8 +/- 0.3 and 4.8 +/- 0.2 h respectively. This was unaffected by GE. The inhibitory action of GE on alpha 1 and beta 1 mRNA levels was accompanied by a dose-dependent decrease in levels of intracellular cAMP (means +/- S.E.M., n = 4) from 395 +/- 28 fmol cAMP/microgram total cell protein to between 275 +/- 19 fmol/micrograms total cell protein (0.1 microM GE) and 78 +/- 11 fmol/micrograms total cell protein (10 microM GE). This was abolished following down-regulation of protein kinase C by prolonged treatment with the phorbol ester tetradecanoylphorbol-13-acetate (TPA), and by pertussis toxin (PT), but not by cholera toxin (CT). Indeed, subunit mRNA levels were increased by 8-bromo-cAMP (2.2-fold) and stimulators of adenylate cyclase activity, i.e. forskolin (2.1-fold), PT (2.1-fold) and CT (1.9-fold), but not by TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transcriptional regulation of Na/K-ATPase by corticosteroids, glycyrrhetinic acid and second messenger pathways in rat kidney epithelial cells. 854 17


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