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)

Endothelins (ETs) are a family of 21-amino acid hypertensive peptides, which together with their receptors ETA and ETB are expressed in human adrenal cortex. Evidence has been provided that ETs exert a potent secretagogue effect on human adrenocortical cells, acting through both ETA and ETB receptors. Therefore, it seemed worthwhile to study the signaling cascades mediating the cortisol secretagogue effect of the two receptor subtypes. Normal adrenal glands were obtained from consenting patients undergoing unilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. Dispersed zona fasciculata-reticularis (ZF/R) cells were obtained by collagenase digestion and mechanical disaggregation. The selective activation of ETA and ETB receptors was obtained by exposing dispersed cells to ET-1 plus the ETB receptor antagonist BQ-788 and to the selective ETB receptor agonist BQ-3020, respectively. ETA and ETB receptors about equally contributed to the cortisol response of dispersed ZF/R cells to ETs. The phospholipase (PL) C inhibitor U-73122 abolished ETA-mediated secretory response, but only partially prevented the ETB-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes, while the Ca(2+)-channel blocker nifedipine was ineffective. The ETB receptor-, but not the ETA receptor-mediated cortisol response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. The inhibitors of adenylate cyclase, PKA, tyrosine kinase and lipoxygenase did not affect the secretory response to the activation of either receptor subtype. ETA-receptor activation raised inositol triphosphate (IP3) production from dispersed ZF/R cells, while ETB-receptor stimulation enhanced both IP3 and prostaglandin-E(2) production. Collectively, our findings indicate that ETs stimulate cortisol secretion from human ZF/R cells, acting through ETA receptors exclusively coupled with PLC/PKC-dependent pathway and ETB receptors coupled with both PLC/PKC- and COX-dependent cascades.
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PMID:Signaling pathways involved in the A and B receptor-mediated cortisol secretagogue effect of endothelins in the human adrenal cortex. 1117 11

Compelling evidence indicates that endothelins (ETs) stimulates aldosterone secretion from rat zona glomerulosa (ZG) cells, acting through the ETB receptor subtype. We have investigated the mechanisms transducing the aldosterone secretagogue signal elicited by the pure activation of ETB receptors. Aldosterone response of dispersed rat ZG cells to the selective ETB-receptor agonist BQ-3020 was not affected by inhibitors of adenylate cyclase/protein kinase (PK)A, tyrosine kinase-, mitogen-activated PK-, cyclooxygenase- and lipoxygenase-dependent pathways. In contrast, the inhibitor of phospholipase C (PLC) U-73122 abrogated, and the inhibitors of PKC, phosphatidylinositol trisphosphate (IP(3))-kinase and calmodulin (calphostin-C, wortmannin and W-7, respectively) partially prevented aldosterone response to BQ-3020. When added together, calphostin-C and wortmannin or W-7 abolished the secretagogue effect of BQ-3020. BQ-3020 elicited a marked increase in the intracellular Ca2+ concentration ([Ca2+]i) in dispersed rat ZG cells, and the effect was abolished by the Ca(2+)-release inhibitor dantrolene. The Ca2+ channel blocker nifedipine affected neither aldosterone nor Ca2+ response to BQ-3020. Collectively, our findings suggest that (1) ETs stimulate aldosterone secretion from rat ZG cells through the activation of PLC-coupled ETB receptors; (2) PLC stimulation leads to the activation of PKC and to the rise in [Ca2+]i with the ensuing activation of calmodulin; and (3) the increase in [Ca2+] is exclusively dependent on the stimulation of IP(3)-dependent Ca2+ release from intracellular stores.
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PMID:Endothelins stimulate aldosterone secretion from dispersed rat adrenal zona glomerulosa cells, acting through ETB receptors coupled with the phospholipase C-dependent signaling pathway. 1117 5

Sensory neurons of the vomeronasal organ (VNO) detect volatile chemicals that are released by conspecific animals and convey information about social and reproductive behavior. The signal transduction pathway in vomeronasal receptor neurons (VRNs) is not known in detail, but is believed to be distinct from that of the sensory neurons of the main olfactory system. Many of the identified olfactory transduction components are not expressed by VRNs. Using Ca2+ imaging and electrophysiological recordings, we investigated the signal transduction pathway of urine perception and the possible role of polyunsaturated fatty acids (PUFAs) as intracellular messengers in freshly dissociated rat VNO neurons. We found that application of urine induced a transient increase in intracellular Ca2+ that was dependent on the activity of phospholipase C and diacylglycerol (DAG) lipase. The Ca2+ transient was not dependent on depletion of intracellular Ca2+ stores but was dependent on the presence of extracellular Ca2+. Furthermore, the urine response was not sensitive to modulators of adenylate cyclase and inhibitors of inositol 1,4,5-trisphosphate receptors. Application of PUFAs (linolenic acid and arachidonic acid, synthesized in living cells from DAG) also elicited Ca2+ transients in fura 2 measurements and inward currents in whole-cell voltage-clamp recordings. Pharmacological inhibition of lipoxygenase and cyclooxygenase induced a transient increase in intracellular Ca2+, possibly by increasing the endogenous level of PUFAs, leading to activation of transduction channels. These data provide evidence for a role of PUFAs in rat vomeronasal signal transduction.
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PMID:Arachidonic acid plays a role in rat vomeronasal signal transduction. 1235 17

Angiotensin (Ang) peptides play a critical role in regulating vascular reactivity and structure. We showed that Ang-(1-7) reduced smooth muscle growth after vascular injury and attenuated the proliferation of vascular smooth muscle cells (VSMCs). This study investigated the molecular mechanisms of the antiproliferative effects of Ang-(1-7) in cultured rat aortic VSMCs. Ang-(1-7) caused a dose-dependent release of prostacyclin from VSMCs, with a maximal release of 277.9+/-25.2% of basal values (P<0.05) by 100 nmol/L Ang-(1-7). The cyclooxygenase inhibitor indomethacin significantly attenuated growth inhibition by Ang-(1-7). In contrast, neither a lipoxygenase inhibitor nor a cytochrome p450 epoxygenase inhibitor prevented the antiproliferative effects of Ang-(1-7). These results suggest that Ang-(1-7) inhibits vascular growth by releasing prostacyclin. Ang-(1-7) caused a dose-dependent release of cAMP, which might result from prostacyclin-mediated activation of adenylate cyclase. The cAMP-dependent protein kinase inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate attenuated the Ang-(1-7)-mediated inhibition of serum-stimulated thymidine incorporation. Finally, Ang-(1-7) inhibited Ang II stimulation of mitogen-activated protein kinase activities (ERK1/2). Incubation of VSMCs with concentrations of Ang-(1-7) up to 1 micromol/L had no effect on ERK1/2 activation. However, preincubation with increasing concentrations of Ang-(1-7) caused a dose-dependent reduction in Ang II-stimulated ERK1/2 activities. Ang-(1-7) (1 micromol/L) reduced 100 nmol/L Ang II-stimulated ERK1 and ERK2 activation by 42.3+/-6.2% and 41.2+/-4.2%, respectively (P<0.01). These results suggest that Ang-(1-7) inhibits vascular growth through the release of prostacyclin, through the prostacyclin-mediated production of cAMP and activation of cAMP-dependent protein kinase, and by attenuation of mitogen-activated protein kinase activation.
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PMID:Molecular mechanisms of inhibition of vascular growth by angiotensin-(1-7). 1295 14

The role of phospholipase C (an enzyme involved in the metabolism of inositol-containing phospholipids), cyclooxygenase and lipoxygenase (the enzymes of arachidonic acid metabolism), and adenylate cyclase and phosphodiesterase (the enzymes of cyclic adenosine 3,5-monophosphate (cAMP) metabolism) in the mechanisms of the aggregation of human platelets induced by the serine protease in low concentrations (thrombin 0.5 mkg per ml, trypsin 1 mkg per ml, and alpha-chymotrypsin 10 mkg per ml) have been investigated with the use of the inhibitor analysis. The effect of neomycin sulfate (phospholipase C inhibitor), indometacin (cyclooxygenase inhibitor), and nordihydrogvayaretic acid (lipoxygenase inhibitor) on protease-induced increase in the content of calcium cations in platelet plasma has been studied. The results of the inhibitor analysis indicated that the enzymes of metabolism of inositol-containing phospholipids, arachidonic acid, and cAMP are involved in the mechanisms of the protease-induced platelet aggregation. The increase in the content of calcium ions, associated with the protease-induced activation of phospholipase C, in cytoplasm may play an important role in the mechanisms of platelet aggregation.
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PMID:[Mechanisms of the protease-induced aggregation of human platelets]. 1790 8

Abstract The potential involvement of arachidonic acid metabolites in the regulation of adenohypophyseal secretion was analysed on pituitary glands from male rats incubated in the presence of various inhibitors with different mechanisms of action: two inhibitors of phospholipase A(2) (parabromophenacylbromide, PB and compound CB 874), an inhibitor of cyclooxygenase- and lipoxygenase-catalysed pathways (5, 8, 11, 14-eicosatetraynoic acid, ETYA) and an inhibitor of cyclooxygenase (epsilon-lysyl acetylsalicylate, ASP). Under conditions which minimize side effects of the drugs, all inhibitors reduced prostaglandin synthesis and release, without affecting the metabolic integrity of the tissues (assessed by their intracellular adenosine triphosphate levels). All agents tested (PB, ETYA, ASP) suppressed prolactin secretion induced either by thyrotropin-releasing hormone or vasoactive intestinal peptide. Basal prolactin secretion was sensitive to phospholipase A(2) inhibitors. Similar inhibitions were obtained with ETYA and CB 874 on growth hormone secretion under basal conditions as well as after stimulation by growth hormone-releasing factor, thyrotropin-releasing hormone, or vasoactive intestinal peptide. In contrast, luteinizing hormone secretion, stimulated or not by gonadotropin-releasing hormone, was not sensitive to any of the agents used. It is concluded that, in intact male hemipituitaries, arachidonic acid metabolism is involved in the stimulation of prolactin and growth hormone secretion by neuropeptides. In contrast, luteinizing hormone release does not seem to depend on that mechanism. It has been verified that the inhibitors of arachidonic acid metabolism do not directly interfere with adenylate cyclase, or with the activation of protein kinase C, two enzymes which are involved in the regulation of secretory mechanisms.
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PMID:Arachidonate metabolism in the anterior pituitary: effect of arachidonate inhibitors on Basal and stimulated secretion of prolactin, growth hormone and luteinizing hormone. I. Hormone release from incubated or perifused pituitary fragments. 1921 71

Abstract In the accompanying study, we reported the effects of inhibitors of arachidonic acid metabolism on the regulation of prolactin, growth hormone (GH) and luteinizing hormone secretion by male hemipituitaries. The present work extends these investigations to primary cell cultures of the same origin. Arachidonic acid metabolism was inhibited by either 5, 8, 11, 14-eicosatetraynoic acid (ETYA), a blocker of cyclooxygenase- and lipoxygenase-catalysed pathways, or the cyclooxygenase inhibitors, indomethacin and aspirin. ETYA inhibited basal GH secretion by 60%, an effect which was reversed by micromolar concentrations of exogenous arachidonic acid. ETYA was much less effective on growth hormone-releasing factor-induced GH release, a result which contrasts with data obtained on intact glands. Growth hormone-releasing factor stimulation of adenylate cyclase was not affected by ETYA. Cyclooxygenase inhibitors decreased basal secretion to a more limited extent (-30%) and were ineffective on growth hormone-releasing factor-stimulated release. Basal prolactin secretion was reduced by 30% in the presence of ETYA and unaffected by cyclooxygenase inhibitors. As with GH, the effect was reversed by exogenous arachidonic acid. However, in contrast to growth hormone-releasing factor-stimulated GH secretion, thyrotropin-releasing hormone stimulation of prolactin release was able to overcome the inhibition by ETYA in a dose-dependent manner. Again, the insensitivity of thyrotropin-releasing hormone-stimulated prolactin release to ETYA contrasts with the data obtained in intact tissue. Moreover, ETYA inhibited (-60%) prostaglandin E(2) production; thyrotropin-releasing hormone was unable to increase the prostaglandin levels in control or ETYA-treated cells. This confirms the data obtained with cyclooxygenase inhibitors, suggesting that prostaglandins are not involved in prolactin secretion. Intracellular accumulation of Ca(2+) by the ionophore A23187 and protein kinase C stimulation by the phorbol ester 12-O- tetradecanoyl phorbol acetate (TPA), strongly stimulated GH and prolactin release. Under these conditions, ETYA was no longer able to inhibit secretion of the hormones. As with intact glands, basal and gonadotropin-releasing hormone or TPA-induced luteinizing hormone secretion were unaffected by any of the inhibitors used. It is concluded that blockade of the arachidonic acid cascade interferes with a secretory pathway involved mainly with basal release of prolactin and GH, but not luteinizing hormone. Thyrotropin-releasing hormone, a secretagogue known to trigger phospholipase C and, hence, to stimulate Ca(2+) mobilization and protein kinase C, overcame ETYA inhibition of prolactin secretion. Growth hormone-releasing factor, a secretagogue recognized by adenylate cyclase coupled receptors, did not overcome ETYA inhibition of GH secretion. However, both secretagogues strongly stimulated hormone release from their target cells in the presence of ETYA. The arachidonic acid cascade thus seems less important in neuromediator-induced secretion coupling processes in dispersed pituitary cells, than in the intact gland. These observations suggest that eicosanoids are more likely to mediate paracrine or autocrine modulations of secretory mechanisms, rather than to function as intracellular messengers.
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PMID:Arachidonate Metabolism in the Anterior Pituitary: Effect of Arachidonate Inhibitors on Basal and Stimulated Secretion of Prolactin, Growth Hormone and Luteinizing Hormone. II. Hormone Release from Dispersed Pituitary Cells. 1921 72


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