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)

Epidermal growth factor (EGF) causes rapid increases in free intracellular Ca2+ and stimulates the phosphorylation of 11 cytosolic proteins in hepatocytes. Ten of the 11 cytosolic proteins altered by EGF are identical to those affected by angiotensin II, a hormone that stimulates the breakdown of phosphatidylinositol 4,5-bisphosphate. An increase in the phosphorylation of the other protein, spot c (Mr = 36,000, pI = 5.5), is observed only with EGF. Treatment of intact rats with pertussis toxin to ADP-ribosylate Ni, the inhibitory GTP-binding protein of the adenylate cyclase complex, abolished the effect of EGF on Ca2+ mobilization and on the phosphorylation of the 10 proteins affected in common with angiotensin II. This treatment had minimal effects on the ability of EGF to stimulate the phosphorylation of its unique substrate, spot c. In marked contrast, modification of Ni did not block the ability of angiotensin II to stimulate Ca2+ mobilization or protein phosphorylation. Pretreatment of normal hepatocytes with 4 beta-phorbol 12-myristate 13-acetate blocked all responses to EGF, including the increased phosphorylation of spot c, but had no effect on the responses to angiotensin II. These results imply that Ni or a similar pertussis toxin substrate may mediate the apparent effects of EGF on phosphatidylinositol breakdown and that protein kinase C may regulate a site in the transduction pathway. Angiotensin II appears to use a different signal transduction mechanism to stimulate phosphatidylinositol metabolism in hepatocytes.
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PMID:Pertussis toxin or phorbol 12-myristate 13-acetate can distinguish between epidermal growth factor- and angiotensin-stimulated signals in hepatocytes. 308 11

Angiotensin II (ANG II) binds with high affinity to specific renal receptors and exerts major influences on hemodynamics and tubular transport. Glomerular and tubular epithelial receptors are well characterized in contrast to pre- and postglomerular and medullary vasculature. Therefore, the scope of this review is limited to an indepth comparison of ANG II receptor kinetics, analogue specificity, and mechanisms of receptor regulation and signal transduction in glomeruli and epithelial cells. Despite the fact that these receptors are in close proximity anatomically, there is evidence from a number of laboratories that permits classification into two distinct receptor subtypes. The receptor of the glomerular mesangium, classified herein as "type A," is characterized by high affinity for ANG II and the heptapeptide, des-Asp1-Ang II (ANG III), "downregulation" with high ambient concentrations of ANG II and signal transduction mediated by phospholipase C-induced Ca2+ transients. The tubular epithelial ANG II receptor, "type B," is of lower affinity for ANG II and ANG III, "upregulated" by high levels of ANG II and mediates inhibition of adenylate cyclase following coupling to an inhibitory GTP binding protein. Both receptors possess secondary mechanisms of signal transduction that may also participate in regulation of cellular function(s). These findings support the hypothesis that at least two distinct classes of ANG II receptors are present in the kidney cortex.
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PMID:Angiotensin receptor subtypes of the kidney cortex. 330 Mar 68

These studies were designed to examine the cellular messenger that mediates the action of angiotensin II on fluid transport (Jv) in the rabbit proximal tubule. We measured the effects of angiotensin II on Jv, activation of adenylate cyclase, and the concentration of cytosolic free calcium (Cai) in the rabbit proximal tubule. In nine rabbit proximal convoluted tubules (PCT), angiotensin II, 10(-8) M and 10(-6) M, decreased Jv by 18 and 25%, P less than 0.05. In eleven rabbit proximal straight tubules (PST), 10(-8) and 10(-6) M angiotensin II decreased Jv by 20 and 23%, P less than 0.02. Angiotensin II did not affect lumen-to-bath phosphate fluxes in PCT or PST, and it did not activate adenylate cyclase in PST. In a preparation of proximal tubules (PCT and PST) loaded with aequorin, angiotensin II, 10(-8) and 10(-6) M, transiently increased Cai by 13 and 32%, P less than 0.001. We propose that Cai surges, activated by angiotensin II, are part of a cellular message that inhibits Jv in the rabbit proximal tubule.
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PMID:Intracellular messenger for action of angiotensin II on fluid transport in rabbit proximal tubule. 382 85

Angiotensin II can elicit cellular responses by 2 different receptor-dependent mechanisms: increase in intracellular calcium or inhibition of adenylate cyclase activity. The well-known inhibition of renin release from granulated cells of the kidney is thought to be mediated by an increase in intracellular calcium. However, the participation of the other possible pathway, i.e. inhibition of adenylate cyclase, has not been excluded. We studied this question by using the toxin from Bordetella pertussis, which inactivates the inhibitory coupling units Ni and thus permits to identify hormonal actions mediated through inhibition of adenylate cyclase. In isolated perfused kidneys from rats pretreated with pertussis toxin (2 micrograms/100 g i.v., single injection) the inhibition of renin release by angiotensin II (10(-11) to 10(-8) M) was significantly attenuated. In parallel, the vasoconstrictor response to angiotensin II was also diminished in these rat kidneys. The effect of pertussis toxin was apparent 3, 5 and 10 days after treatment, with a maximal effect at the fifth day. These data suggest that angiotensin II may exert the inhibitory effect on renin release in part through inhibition of adenylate cyclase in granulated cells of the kidney.
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PMID:Pertussis toxin attenuates angiotensin II-induced vasoconstriction and inhibition of renin release. 393 13

Hepatic plasma membranes of female obese mice C57 BL-6 orl ob/ob (ob/ob mice) completely lack vasopressin (VP) receptors of the V1 type whereas kidney VP receptors are normally expressed and functionally coupled to adenylate cyclase. To discover if these alterations are linked to a genetic defect of the V1 receptor, we have studied the binding of VP on liver and kidney membranes of two other models, female diabetic mice C57 BL-6 orl db/db (db/db mice) and female Zucker rats Fatty/orl fa/fa (fa/fa rats), which exhibit different temporal pattern of obesity, hyperinsulinemia and insulin resistance. In addition, since VP is known to exert its vascular response through stimulation of V1 receptors, we have studied the reactivity of VP of isolated tail artery in the three different models, ob/ob and db/db mice and fa/fa rats, and in their respective controls. In all cases, VP kidney receptors and VP vascular reactivity are normal. db/db mice exhibit a marked decrease in hepatic VP receptors whereas a 50% decrease was observed in 32 week fa/fa rats. Angiotensin II and prazosin binding sites are still present as well as the adenylate cyclase response to glucagon. These results suggest that the specific alteration in liver VP receptors is not related to a defect in V1 receptor genetic expression but is specific for liver and appears to parallel the level of hyperinsulinemia and/or insulin resistance.
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PMID:Reduction in hepatic but not in renal and vascular vasopressin receptor number in hyperinsulinemic mice and rats. 609 84

Choline esters fail to depress developed tension or the maximum upstroke velocity (Vmax) of slow action potentials in embryonic chick ventricles, but they inhibit the stimulatory effect of the phosphodiesterase inhibitor methylisobutylxanthine (MIX). The mechanism by which the choline ester methacholine (MCh) counteracts the effects of MIX was examined in ventricular myocardium obtained from 7-day-old embryonic chicks. Four possible hypotheses were 1) that the physiological response to MCh is mediated by cyclic GMP, the production of which is potentiated by MIX; 2) that MCh acts by a mechanism independent of cyclic nucleotides; 3) that the binding of MIX to adenosine receptors induces sensitivity to MCh; or 4) that MCh acts by depressing basal cyclic AMP levels. Interactions between MCh, Angiotensin II and a nonmethylxanthine phosphodiesterase inhibitor (Ro 7-2956) were assessed by measuring tissue levels of cyclic nucleotides and the Vmax of slow action potentials. MCh significantly reduced the basal cyclic AMP level of embryonic chick ventricles, despite having no physiological effect. The results favor the final hypothesis and imply that MCh effects are mediated by inhibition of adenylate cyclase activity. The physiological response of the myocardium to a reduction in basal adenylate cyclase activity appears to be dependent on the initial tissue level of cyclic AMP.
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PMID:Sensitivity of Ca-dependent slow action potentials to methacholine is induced by phosphodiesterase inhibitors in embryonic chick ventricles. 617 16

Guanine nucleotides were observed to modify the binding of 125I-angiotensin II to rat hepatic plasma membrane receptors. GTP and its nonhydrolyzable analogues greatly increased the dissociation rate of bound 125I-angiotensin II and altered hormone binding to the receptor under equilibrium conditions. In the absence of GTP, 125I-angiotensin II labeled both high affinity sites (Kd1 = 0.46 nM, N1 = 650 fmol/mg) and low affinity sites (Kd2 = 4.1 nM, N2 = 1740 fmol/mg). In the presence of guanine nucleotides, the affinities of the two sites were unchanged, but the number of high affinity sites decreased markedly to 52 fmol/mg. In analogous experiments using the angiotensin II antagonist, 125I-sarcosine1,Ala8-angiotensin II (125I-saralasin), guanine nucleotides minimally affected the interaction of 125I-saralasin with its receptor, increasing the dissociation rate 1.9-fold and the Kd 1.4-fold. The guanine nucleotide inhibition of agonist binding required a cation such as Na+ or Mg2+, with a maximal effect occurring at about 1 mM Mg2+. In liver plasma membranes prepared in EDTA, angiotensin II inhibited basal and glucagon-stimulated adenylate cyclase activities by 30% and 10%, respectively. Angiotensin II also caused a 40% inhibition of glucagon-stimulated cyclic AMP accumulation in intact hepatocytes, with a half-maximal effect occurring at 1 nM. The inhibition by angiotensin II of adenylate cyclase in membranes and of cAMP levels in intact cells could be reversed by the antagonist sarcosine1,Ile8-angiotensin II. Vasopressin caused a smaller 26% inhibition of glucagon-stimulated cyclic AMP accumulation. The ability of angiotensin II to inhibit cyclic AMP synthesis may provide an explanation for the observed effects of guanine nucleotides on 125I-angiotensin II binding to plasma membranes.
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PMID:The hepatic angiotensin II receptor. II. Effect of guanine nucleotides and interaction with cyclic AMP production. 627 54

Cultured endothelial cells derived from cerebral microvessels separated from 2-day-old rat brain contain a specific beta 2 and alpha 2-adrenergic sensitive adenylate cyclase (AC). Among the various tested hormones, PGE1 and PGE2 were found to be the most potent activators, while adenosine, angiotensin I and II, gamma-aminobutyric acid and vasoactive intestinal peptide inhibited the enzyme activity. However, acetylcholine, histamine, serotonin, glycine, glutamine, bradykinin, neurotensin and vasopressin (Lysine and Arginine) had no effect on the adenylate cyclase activity in this model. The susceptibility of the cerebrovascular endothelial AC system to the vasoactive substances as well as presence of beta 2 and alpha 2-type adrenergic receptors in the cultured endothelium provides additional support for the proposed endothelial involvement in the regulation of cerebrovascular permeability and blood flow.
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PMID:Cerebral endothelial cell culture. I. The presence of beta 2 and alpha 2-adrenergic receptors linked to adenylate cyclase activity. 627 96

Angiotensin II binding sites in a rabbit ventricular myocardial particulate fraction were identified and characterized with the radioligand 125I-angiotensin II. The order of potency in competing with 125I-angiotensin II for these sites was similar to that observed in physiological studies. Computer-assisted analysis of the competition of binding sites for 0.3 nM 125I-angiotensin II by unlabeled angiotensin II (3 X 10(-11) M to 1 X 10(-5) M) demonstrated that optimal fitting of the competition curves was attained with a two-site model having one site of high affinity (KA1 = 2.4 +/- 0.6 X 10(9) M-1), low capacity (N1 = 7.8 +/- 0.8 fmoles/mg of protein) and a second site low affinity (KA2 = 9.6 +/- 0.6 X 10(6) M-1) and high capacity (N2 = 219 +/- 128 fmoles/mg of protein). Analysis of competition by Sar1-Ile8 angiotensin II for 125I-angiotensin II binding sites indicated that the antagonist interacted with the first site with high affinity (KA1 = 8 X 10(9) M-1), but interacted minimally with the second site (KA2 = 10(5) M-1). Monovalent cations (Na+, K+, Li+, NH4+) were roughly equipotent in decreasing 125I-angiotensin II binding by reducing the number of high-affinity sites (N1 = 2.6 +/- 0.7 fmoles/mg of protein with 100 mM Na+) without changing the affinity of either site or the number of low-affinity sites. The number of high-affinity sites was increased to 14.4 +/- 1.5 fmoles/mg of protein by 5 mM Mg2+. In the presence of divalent cations, nucleotides reduced binding of 125I-angiotensin II with the potency order guanosyl-5'-yl-imidodiphosphate greater than GTP greater than GDP greater than ATP greater than GMP. Guanosyl-5'yl-imidodiphosphate significantly reduced the affinity of the high-affinity site (KA1 = 1.0 +/- 0.2 X 10(9) M-1) and perhaps of the low-affinity site (KA2 = 1.0 +/- 2.2 X 10(6) M-1). Computer-assisted assessment of dissociation of 0.3 nM 125I-angiotensin II from rabbit myocardial membranes corroborated the equilibrium data: dissociation was biphasic (K-1 = 0.19 +/- 0.2 min-1 for a rapidly dissociating site, k-1 = 2.5 +/- 2.1 X 10(-3) min-1 for a slowly dissociating site); 5 mM Mg2+ did not significantly change either dissociation rate; but guanosyl-5'-yl-imidodiphosphate significantly increased dissociation rates from both sites. Despite the indirect evidence that these angiotensin II receptors interact with guanine nucleotide regulatory proteins, angiotensin II (10(-6) M) failed to influence adenylate cyclase activity. The physiological implications of the presence in ventricular myocardium of two distinct angiotensin II receptors and in particular the implications of a receptor-associated guanine nucleotide regulatory protein which does not couple to adenylate cyclase require further investigation.
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PMID:Characterization of the rabbit ventricular myocardial receptor for angiotensin II. Evidence for two sites of different affinities and specificities. 631 Mar 63

Angiotensin II (AII) inhibited adenylate cyclase from rat aorta in a concentration dependent manner. The maximal inhibition (approximately 20%) was observed at 10 microM. The inhibitory effect of angiotensin II was dependent on monovalent cations such as Na+ or Li+ and was blocked by saralasin, an antagonist of angiotensin. Guanine nucleotides such as GTP or GMP-P (NH)P were also required to elicit the inhibition by angiotensin II. In addition, angiotensin II also inhibited the stimulation exerted by catecholamines. These data suggest that angiotensin receptors are present in aorta which are negatively coupled to adenylate cyclase.
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PMID:Angiotensin II receptors negatively coupled to adenylate cyclase in rat aorta. 631 57


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