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)

Angiotensin II (AngII) is a potent regulator of electrolyte transport with biphasic effects on salt and HCO3-resorption in proximal tubule epithelia (PCT). In cultured PCT cells, pM to nM AngII activates a GTP-binding protein to inhibit cAMP formation and thus releases inhibition of apical Na/H exchange. Phospholipase A2 is activated by nM to microM AngII releasing arachidonate which is metabolized by a novel P450 epoxygenase to form 5,6-epoxy-eicosatrienoic acid (5,6-EET). 5,6-EET and nM apical AngII cause dihydropyridine-sensitive Ca2+ influx from the extracellular space, inhibition of apical-to-basolateral Na flux, and decrease in epithelial monolayer short circuit current. 5,6-EET also inhibits Na/K-ATPase by 50%. This P450 epoxygenase is physiologically important in the AngII-signaling system because the P450 inhibitor ketoconazole blocks AngII effects while potentiating exogenous 5,6-EET effects. Finally, these AngII-mediated signaling systems are polarized in the PCT with pM basolateral AngII inhibiting adenylate cyclase and nM apical AngII activating PLA2 and subsequent generation of 5,6-EET.
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PMID:Angiotensin II actions in the rabbit proximal tubule. Angiotensin II mediated signaling mechanisms and electrolyte transport in the rabbit proximal tubule. 170 6

To examine the mechanisms which regulate the functions of the intercalated cells (ICs) in the cortical collecting duct (CCD), the effect of isoproterenol on intracellular pH (pHi) of ICs was studied with the in vitro microperfused rabbit CCD, using the single cell pHi determination technique with fluorescent dye, 2',7'-bis-(2-carboxyethyl)-5(and-6)carboxyfluorescein. The pHi of beta-IC was significantly decreased with the addition of basolateral 10(-6) M isoproterenol (7.21 +/- 0.04 to 7.05 +/- 0.04), whereas alpha-IC did not show any change. This response of beta-IC to isoproterenol was dose-dependent and completely inhibited by the beta-blockers, atenolol or propranolol. The addition of forskolin or 8-Br-cAMP mimicked the effects of isoproterenol, suggesting that the activation of adenylate cyclase induced the decrease in pHi. The rate of pHi changes after the Cl- removal from the perfusate, which is considered to reflect the activity of luminal anion exchanger, was significantly higher with isoproterenol (0.032 +/- 0.009 pH unit/s) than that in the control (0.023 +/- 0.009 pH unit/s). The present studies provide direct evidence for the regulation of beta-IC function by beta-adrenergic receptor; and the luminal Cl-/HCO3- exchanger was considered to be stimulated by beta-agonist, directly.
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PMID:Effect of isoproterenol on intracellular pH of the intercalated cells in the rabbit cortical collecting ducts. 184 43

The tetradecapeptide somatostatin-14 (SS-14) has been found to alter electrogenic ion transport in the rat, guinea pig and rabbit intestinal mucosa in vitro. In this study, the actions of SS-14 and related peptides on mucosal ion transport were investigated in the intestinal tract of the pig, a species whose digestive physiology is similar to man. The contraluminal- but not luminal-side administration of SS-14 (1-1000 nmol/l) to sheets of mucosa-submucosa obtained from different regions of the porcine small intestine and colon produced rapid, sustained decreases in short-circuit current (lsc), a measure of active ion transport, that were localized to segments of the distal jejunum. The magnitude of this peptide action was greater in tissues manifesting a serosapositive basal potential difference greater than 0 mV than in those displaying a spontaneous potential difference less than 0 mV. Under basal conditions, SS-14 produced a maximum decrease in distal jejunal lsc which was nearly twice that produced by its synthetic analog SMS 201,995 (octreotide); the two peptides inhibited lsc with similar potencies. SS-14 (10 nmol/l) increased the lumen-to-serosa transepithelial Cl flux and eliminated net residual flux. Mucosal lsc responses to SS-14 were absent in tissues bathed in HCO3-free media. Peptide actions were generally resistant to inhibitors of epithelial anion exchange, Na-proton exchange and NaCl cotransport. The adenylate cyclase activator forskolin (1 mumol/l) and the cyclic AMP analog 8-bromo-cyclic AMP (0.3 mmol/l) evoked net Cl secretion which was associated with rapid and sustained elevations in lsc.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurohormonal regulation of ion transport in the porcine distal jejunum. Actions of somatostatin-14 and its natural and synthetic homologs. 196 42

Plasma membranes were purified from flagella of porcine cauda epididymal sperm and proteolytic regulation of bicarbonate-sensitive adenylate cyclase was studied. It was found that the epididymal sperm plasma membrane contained a trypsin-like proteinase which inactivated adenylate cyclase. Bicarbonate activates adenylate cyclase as reported previously, but, at the same time, the anions enhance the inactivation of the enzyme by the membrane-bound trypsin-like proteinase. This phenomenon is not due to the direct activation of the proteinase, but closely related to the activation of adenylate cyclase by bicarbonate. It was also found that seminal proteinase inhibitors blocked the inactivation of adenylate cyclase and maintained the bicarbonate activation of the enzyme at high level. Actually, bicarbonate keeps adenylate cyclase fully active in ejaculated sperm, because membrane-bound proteinase is completely inhibited by the seminal proteinase inhibitors. These results suggest that the interactions between membrane-bound proteinase and seminal proteinase inhibitor are involved in the regulation of the bicarbonate-sensitive adenylate cyclase system.
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PMID:Effects of a membrane-bound trypsin-like proteinase and seminal proteinase inhibitors on the bicarbonate-sensitive adenylate cyclase in porcine sperm plasma membranes. 216 77

1. In order to distinguish between models of anion secretion, the effects of transport inhibitors on saliva flow rate and electrolyte composition were studied during the plateau phase of secretion in rabbit mandibular salivary glands. 2. Bumetanide, an inhibitor of Na+,K+,2Cl- co-transport, inhibited flow rate (by 60%) and reduced Cl- concentration. K+ and HCO3- concentrations were increased. Forskolin, an adenylate cyclase activator which inhibits ductal transport, did not significantly affect this pattern of changes. 3. Amiloride, used at concentrations that would inhibit Na(+)-H+ exchange, inhibited flow rate (by 30%). Cl- concentration was initially increased before subsequently decreasing at the same time as HCO3- concentration increased. These concentration changes can probably be attributed to ductal transport. When amiloride was applied to glands perfused with nominally HCO3- -free solutions, inhibition of flow rate was rapid and almost complete. 4. When amiloride and bumetanide were both present in the perfusate, flow rate was inhibited by 92%. The pattern of electrolyte changes was not significantly different from that observed in the presence of bumetanide alone. 5. Inhibition of K+ channel activity using Ba2+ also inhibited flow rate. Cl- concentration was increased as was K+ concentration. HCO3- concentration was not increased. 6. The anion exchange inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) had no effect on either flow rate or electrolyte concentration. It did, however, elicit secretion in the absence of acetylcholine. 7. The data suggest that Na(+)-H+ and Cl- -HCO3- exchangers are unlikely to be involved in fluid and electrolyte secretion in these glands as suggested by some authors. Most of the data can be explained by postulating the existence of non-specific anion channels in the apical membranes of the acinar cells.
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PMID:The effects of bumetanide, amiloride and Ba2+ on fluid and electrolyte secretion in rabbit salivary gland. 221 84

The characteristics of high affinity [3H]5-HT (5-hydroxytryptamine) binding to non 5-HT1A non 5-HT1C sites were examined in crude membranes prepared from different regions of guinea-pig and pigeon brains. The coupling of these sites to adenylate cyclase was examined, and its pharmacological profile investigated. In the presence of 100 nmol/l 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) and 100 nmol/l mesulergine, [3H]5-HT labelled with nanomolar affinity an apparently homogeneous population of recognition sites in guinea-pig and pigeon brain membranes. The rank order of affinities of agonists and antagonists (5-CT (5-carboxamidotryptamine) greater than 5-HT greater than RU 24969 (5-methoxy-3-(1,2,3,6-tetrahydro-4- pyridinyl)-1H indole succinate) greater than yohimbine greater than or equal to rauwolscine greater than DP-5-CT (N,N dipropyl-5-carboxamidotryptamine) greater than or equal to mianserin greater than 8-OH-DPAT greater than mesulergine greater than SDZ 21-009 ((+/-)-4(3-tert-butyl-amino-2-hydroxypropoxy)-indol-2 carbonic acid isopropyl ester) greater than (-)propranolol), as well as their individual pKD values, were very similar to those at porcine caudate 5-HT1D sites and clearly different from those at rat cortex 5-HT1B sites. In the substantia nigra of the guinea-pig the 5-HT receptor-mediated inhibition of forskolin-stimulated adenylate cyclase had a pharmacological profile fully comparable to that of 5-HT1D binding sites (5-CT greater than 5-HT greater than yohimbine greater than RU 24969 greater than 8-OH-DPAT greater than SDZ 21-009 = isamoltane greater than (-)pindolol greater than (-)propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-HT1D receptors in guinea-pig and pigeon brain. Radioligand binding and biochemical studies. 253 24

Intracellular microelectrode techniques were employed to study the effect of cyclic AMP on apical membrane Cl-/HCO3- exchange and electrodiffusive HCO3- transport in Necturus gallbladder epithelium. Intracellular cAMP levels were raised by addition of either the phosphodiesterase inhibitor theophylline (3 X 10(-3) M) or the adenylate cyclase activator forskolin (10(-5) M) to the serosal bathing solution. Measurements of pH in a poorly buffered control mucosal solution upon stopping superfusion show acidification, owing to secretion of both H+ and HCO3-. When the same experiment is performed after addition of amiloride or removal of Na+ from the mucosal bathing medium, alkalinization is observed since H+ transport is either inhibited or reversed, whereas HCO3- secretion persists. The changes in pH in both amiloride or Na-free medium were significantly decreased in theophylline-treated tissues. Theophylline had no effect on the initial rates of fall of intracellular Cl- activity (aCli) upon reducing mucosal solution [Cl-] to either 10 or 0 mM, although membrane voltage and resistance measurements were consistent with stimulation of apical membrane electrodiffusive Cl- permeability. Estimates of the conductive flux, obtained by either reducing simultaneously mucosal [Cl-] and [HCO3-] or lowering [Cl-] alone in the presence of a blocker of anion exchange (diphenylamine-2-carboxylate), indicate that elevation of intracellular cAMP inhibited the anion exchanger by approximately 50%. Measurements of net Cl- uptake upon increasing mucosal Cl- from nominally zero to levels ranging from 2.5 to 100 mM suggest that the mechanism of inhibition is a decrease in Vmax. Consistent with these results, the rate of intracellular alkalinization upon reducing external Cl- was also inhibited significantly by theophylline. Reducing mucosal solution [HCO3-] from 10 to 1 mM under control conditions caused intracellular acidification and an increase in aCli. Theophylline inhibited both changes, by 62 and 32%, respectively. These data indicate that elevation of intracellular cAMP inhibits apical membrane anion (Cl-/HCO3-) exchange. Studies of the effects of rapid changes in mucosal [HCO3-] on membrane voltages and the apparent ratio of membrane resistances, both in the presence and in the absence of theophylline, with or without Cl- in the mucosal solution, do not support the hypothesis that cAMP produces a sizable increase in apical membrane electrodiffusive HCO3- permeability.
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PMID:Cyclic AMP inhibits Cl-/HCO3- exchange at the apical membrane of Necturus gallbladder epithelium. 282 Nov 59

In cultured cells derived from isolated micromeres of sea urchin eggs, H+,K+-ATPase activity, which became detectable simultaneously with the initiation of spicule formation, was localized in the plasma membrane and the microsome fractions. Activities of marker enzymes for plasma membrane, 5'-nucleotidase, Na+,K+-ATPase, and adenylate cyclase, were found to be high in the plasma membrane fraction. Considerable activity of rotenone-insensitive NADPH-cytochrome c reductase, a marker enzyme for microsome, was detectable in the microsome fraction. These fractions exhibited barely any appreciable activity of markers for the other organellae. H+,K+-ATPase in plasma membrane probably mediates H+ release from the cells, in which H+ is produced in overall reaction to form CaCO3, the main component of spicules, from Ca2+, CO2 and H2O. Cl-,HCO3(-)-ATPase activity was also found in these two fractions before and after the initiation of spicule formation. After initiation, the skeletal vacuole fraction was obtained from subcellular structures containing spicules. Considerable activity of Cl-,HCO3(-)-ATPase was observed in this fraction, which exhibited a weak activity of UDP-galactose: N-acetylglucosamine galactosyltransferase, a marker enzyme for Golgi body. Cl-,HCO3(-)-ATPase in the skeletal vacuole membrane probably mediates HCO3- transport into the vacuoles to supply HCO3- for spicule formation.
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PMID:Distributions of H+,K+-ATPase and Cl-,HCO3(-)-ATPase in micromere-derived cells of sea urchin embryos. 283 20

Bicarbonate ion, the local anesthetics procaine and dibucaine, and the ionophores monensin and nigericin have been shown to markedly increase the ability of agents that elevate cyclic adenosine monophosphate (cAMP) levels to initiate motility in bovine caput spermatozoa. A number of other weak bases, including theophylline, D-600 and dipyridamole, elevate cAMP levels maximally in caput sperm at low levels but induce motility only at high levels. These compounds thus appear to have a dual role in the initiation of motility, i.e., they elevate both cAMP levels and internal pH. Confirmation of this view was provided by the demonstration that bicarbonate ion and procaine permit initiation of motility by theophylline, D-600 and dipyridamole at markedly reduced levels. Also, forskolin (a neutral adenylate cyclase activator) elevates cyclic AMP levels in caput sperm but initiates motility only in the presence of bicarbonate or procaine, and the membrane-permeant cAMP analogue 8-bromo-cAMP is capable of inducing motility only in the presence of bicarbonate. Thus, motility in caput sperm is induced only under conditions that elevate both intracellular cAMP and pH, whereas caudal sperm motility is stimulated by an elevation of either cAMP or pH. These data suggest that the epididymal development of motility requires a maturational increase in internal pH. This suggestion was confirmed by direct measurement of the internal pH of caput and caudal sperm; the internal pH of the former was found to be 5.84 +/- 0.1 and the latter 6.27 +/- 0.05.
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PMID:Evidence for a role for cellular alkalinization in the cyclic adenosine 3',5'-monophosphate-mediated initiation of motility in bovine caput spermatozoa. 298 38

We studied the effects of cyclic AMP (cAMP) on HCO-3 transport by rabbit cortical collecting tubules perfused in vitro. Net HCO-3 secretion was observed in tubules from NaHCO3- loaded rabbits. 8-Bromo-cAMP-stimulated net HCO-3 secretion, whereas secretion fell with time in control tubules. Both isoproterenol and vasopressin (ADH) are known to stimulate adenylate cyclase in this epithelium; however, only isoproterenol stimulated net HCO-3 secretion. The mechanism of cAMP-stimulated HCO-3 secretion was examined. If both HCO-3 and H+ secretion were to occur simultaneously in tubules exhibiting net HCO-3 secretion, cAMP might increase the net HCO-3 secretory rate by inhibiting H+ secretion, by stimulating HCO-3 secretion, or both. These possibilities were examined using basolateral addition of the disulfonic stilbene (4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS). In acidifying tubules from NH4Cl-loaded rabbits, DIDS eliminated HCO-3 reabsorption, a result consistent with known effects of DIDS as an inhibitor of H+ secretion. In contrast, cAMP left acidification (H+ secretion) intact. DIDS applied to HCO-3 secretory tubules failed to increase the HCO-3 secretory rate, indicating minimal H+ secretion in HCO-3 secreting tubules. Thus, inhibition of H+ secretion by cAMP could not account for the cAMP-induced stimulation of net HCO-3 secretion. cAMP-stimulated HCO-3 secretion was reversibly eliminated by 0 Cl perfusate, whereas luminal DIDS had no effect. Bath amiloride (1 mM) failed to eliminate cAMP-stimulated HCO-3 secretion when bath [Na+] was 145 mM or 5 mM. cAMP depolarized the transepithelial voltage. The collected fluid [HCO-3] after cAMP could be accounted for by electrical driving forces, suggesting that cAMP stimulates passive HCO-3 secretion. However, cAMP did not alter HCO-3 permeability measured under conditions expected to inhibit transcellular HCO-3 movement (0 Cl- solutions and bath DIDS). This measured HCO-3 permeability was not high enough to account, by passive diffusion, for the HCO-3 fluxes observed in Cl-containing solutions. We conclude the following: cAMP increased net HCO3- secretion by stimulating HCO3- secretion and not by inhibiting H+ secretion; this HCO3- secretion may have occurred by Cl-HCO3- exchange; Na+-H+ exchange appeared not to play a role in basolateral H+ extrusion under these conditions; and the stimulation of HCO3- secretion by isoproterenol, but not ADH, suggests the existence of separate cell cAMP pools or cellular heterogeneity in this cAMP response.
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PMID:Cyclic adenosine monophosphate-stimulated bicarbonate secretion in rabbit cortical collecting tubules. 298 40


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