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)

Since the kidney medulla was reported to generate platelet activating factor (PAF), we investigated a possible effect of this agent on the reabsorptive function of in vitro microperfused medullary thick ascending limbs from mouse kidney (mTAL). PAF, 10(-7) M in the bath, significantly decreased the net chloride flux (JCl) from 48.8 +/- 7.1 to 27.4 +/- 5.7 pmol/min. This effect was reversible, blocked by the antagonist BN 50730, and not reproduced by the inactive metabolite lyso-PAF. PAF inhibited the transepithelial potential difference with a threshold at 10(-9) M. In the presence of isoproterenol, the PAF-induced decrease of JCl was not significantly different from that observed in basal conditions; moreover, PAF did not modify the adenylate cyclase activity in isolated mTALs, either in basal condition or under stimulation by isoproterenol. The effect of PAF on JCl was not prevented by mepacrine, NDGA associated with proadifen, or adenosine desaminase. When the apical Na-K-2Cl cotransport was blocked by furosemide or bumetanide, a net K secretion occurred (-1.1 +/- 0.2 pmol/min), which was significantly decreased by PAF (-0.06 +/- 0.3 pmol/min). Moreover, it was verified on isolated mTALs that PAF did not modify the Na,K-ATPase activity. It is concluded that PAF inhibits the reabsorptive function of the mTAL, as indicated by the decrease of Cl reabsorption and K secretion. This effect could not be accounted for by adenosine or arachidonic acid metabolite action, and was not mediated by an inhibition of the adenylate cyclase activity.
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PMID:Platelet activating factor inhibits Cl and K transport in the medullary thick ascending limb. 155

In rat olfactory bulb homogenate, carbachol stimulated adenylate cyclase activity in a concentration-dependent manner (EC50 = 1.1 microM). The carbachol stimulation occurred fully in membranes that had been prepared in the presence of 1 mM EGTA and incubated in a Ca2(+)-free enzyme reaction medium. Under these conditions, exogenous calmodulin (1 microM) failed to stimulate adenylate cyclase activity. In miniprisms of olfactory bulb, carbachol (1 mM) increased accumulation of inositol phosphates, but this response was markedly reduced in a Ca2(+)-free medium. Moreover, the carbachol stimulation of adenylate cyclase activity was not affected by staurosporine at a concentration (1 microM) that completely blocked the stimulatory effect of phorbol 12-myristate 13-acetate, an activator of Ca2+/phospholipid-dependent protein kinase. Quinacrine, a nonselective phospholipase A2 inhibitor, reduced the carbachol stimulation of adenylate cyclase activity, but this inhibition appeared to be competitive with a Ki of 0.2 microM. Nordihydroguaiaretic acid and indomethacin, two inhibitors of arachidonic acid metabolism, failed to affect the carbachol response. These results indicate that in rat olfactory bulb, muscarinic receptors stimulate adenylate cyclase activity through a mechanism that is independent of Ca2+ and phospholipid hydrolysis.
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PMID:Ca2(+)-independent stimulation of adenylate cyclase activity by muscarinic receptors in rat olfactory bulb. 211 49

The action of pharmacologic agents on chymase-induced exocytosis of beta-hexosaminidase and arachidonic acid (AA) metabolism by rat serosal mast cells (RSMC) was determined and compared with their effects on anti-IgE induced activation. Indomethacin (INDO) (less than or equal to 10 microM), a cyclooxygenase inhibitor, did not affect chymase- or anti-IgE-mediated exocytosis, while completely inhibiting prostaglandin D2 (PGD2) release at 1.25 microM. Theophylline (THEO), mepacrine, 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C), and diethylcarbamazine (DEC), inhibitors of adenosine binding and phosphodiesterases, phospholipases, AA metabolism, and vesicular transport as well as leukotriene A4 formation, respectively, inhibited exocytosis with ID50 values of 3.4, 0.22, 3.4 and 1.9 mM for chymase and 2.4, 0.17, 2.8 and 5.2 mM for anti-IgE. These agents inhibited net PGD2 release with ID50 values of 2.1, 0.04, less than 0.05, and 1.5 mM for chymase and of 0.5, 0.1, less than 0.05, and 4 mM for anti-IgE. 5,6-Dehydroarachidonic acid (DHA) and arachidonyl hydroxylamine (AH), 5-lipoxygenase inhibitors, did not affect chymase-mediated exocytosis; anti-IgE-mediated exocytosis was not altered by AH but was suppressed by DHA (ID50 = 20 microM). Nordihydroguaiaretic acid (NDGA), an antioxidant, inhibited chymase-mediated exocytosis dose-dependently (ID50 less than or equal to 13.3 microM) while decreasing anti-IgE-mediated exocytosis by only 30% at 2.5-20 microM; net PGD2 release induced by both stimuli was inhibited dose-dependently. 2',5'-Dideoxyadenosine (DDA) and 1,6-di(0-(carbamoyl)cyclohexanone oxime)hexane (RHC 80267) and inhibitors of adenylate cyclase and of di-triglyceride lipases, respectively, had little effect on exocytosis induced by chymase but inhibited that induced by anti-IgE with ID50 values of 0.4 mM and 37 microM, respectively. With DDA the inhibition of net PGD2 release occurred with anti-IgE but not chymase, whereas RHC 80267 inhibited both chymase and anti-IgE-mediated PGD2 release. Differential inhibition of activation-secretion suggests either that chymase provides a step inhibited in IgE-mediated exocytosis by DDA, RHC 80267 and DHA, or that the activating pathway initiated by chymase is distinct.
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PMID:Pharmacological modulation of activation-secretion of rat serosal mast cells by chymase, an endogenous secretory granule protease. 393 69

Calcitonin gene-related peptide (CGRP) added to the internal fluid bathing the isolated skin of Rana esculenta strongly stimulates the active sodium absorption. This action is dose-dependent, the dose eliciting the maximal effect being 2 . 10(-7) M; alpha and beta CGRP exhibit the same potency. The CGRP action on sodium transport is mainly due to its interaction with CGRP1 receptors, since it is inhibited by CGRP8-37, its specific antagonist. The second messengers probably involved in the action of CGRP are cAMP and Ca+2, since this action is reduced by SQ22536 and W7, which are inhibitors of adenyl cyclase and calmodulin respectively. On the contrary, inhibitors of protein kinase C (1-O-hexadecyl-2-O-methyl-sn-glycerol) and nitric oxide synthase (L-NAME) do not modify the action on sodium transport. ETYA, an inhibitor of all the metabolic pathways of arachidonic acid, decreases the CGRP action by 38%. In order to search for the arachidonic acid metabolites involved in the CGRP action, the effect of the following inhibitors was tested: aspirin and naproxen (for cyclooxygenases), NDGA (for cyclooxygenases), NDGA (for lipoxygenases) clotrimazole (for epoxygenases). None of these substances is able to inhibit the CGRP action on sodium transport. Moreover, adding arachidonic acid inhibits the CGRP action, but this effect was also obtained by another unsaturated fatty acid, oleic acid. Since unsaturated fatty acids are able to inhibit the protein kinase A, these results indirectly support the role of cAMP as a second messenger of the CGRP action on sodium transport.
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PMID:Effect of calcitonin gene-related peptide on sodium absorption through isolated skin of Rana esculenta. 881 96

In goldfish, growth hormone (GH) release is stimulated by dopamine via D1 receptors and cAMP-dependent mechanisms and by gonadotropin-releasing hormone (GnRH) through a protein kinase C (PKC) pathway; in addition, both D1 and GnRH actions require extracellular Ca2+. In this study, the involvement of arachidonic acid (AA) and calmodulin (CaM) in mediating the GH responses to D1 and GnRH stimulation was examined using primary cultures of dispersed goldfish pituitary cells. In 2-hr static incubation experiments, the phospholipase A2 inhibitor bromophenacylbromide (BPB; 50 microM) decreased the GH responses to the D1 agonist SKF38393 (1 microM), the adenylate cyclase activator forskolin (10 microM), and the cAMP analog 8Br-cAMP (1 mM), but not the responses to salmon (s)GnRH (100 nM), chicken (c)GnRH-II (100 nM), and AA (50 microM). Similarly, the phospholipase A2 inhibitor quinacrine (50 microM) and an inhibitor of AA metabolism, nordihydroguaiaretic acid (NDGA; 50 microM), reduced the GH responses to SKF38393, forskolin, and 8Br-cAMP. The response to the dopamine agonist apomorphine (1 microM) was also decreased by NDGA. The GH responses to AA did not add to those of forskolin or SKF38393, but were additive to responses to sGnRH and the PKC activator tetradecanoyl phorbol acetate (TPA; 100 nM). In perifusion experiments, treatment with BPB reduced the acute GH response to 1 microM SKF38393, 10 microM forskolin, or 1 mM 8Br-cAMP. Taken together, these results suggest that mobilization and metabolism of AA mediate both acute and prolonged GH responses to D1, but not GnRH. The involvement of AA probably occurs distal to D1-induced cAMP generation. Two-hour static incubation with 10 nM to 10 microM KN62, a CaM-dependent kinase II inhibitor, decreased the GH response to 100 nM sGnRH or cGnRH-II. KN62 (1 microM) similarly decreased the GH response to 1 mu M SKF38393, 10 microM forskolin, 1 mM 8Br-cAMP, or 100 nM TPA. In perifusion studies, KN62 (1 microM) also reduced the acute GH response to 5 min pulses of 100 nM sGnRH, 100 nM cGnRH-II, or 1 microM SKF38393. These results indicate that CaM mediates the acute, as well as the prolonged, GH responses to GnRH and dopamine. The involvement of CaM likely occurs distal to cAMP and PKC.
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PMID:Role of arachidonic acid and calmodulin in mediating dopamine D1- and GnRH-stimulated growth hormone release in goldfish pituitary cells. 886 Mar 13

The GH secretory mechanism of GH-releasing hexapeptide (GHRP-6), GHRH, and TRH were studied in vivo and in vitro in seven patients with acromegaly. In an in vivo study, these patients showed clear GH responses to single administration of GHRP (four of four patients), GHRH (seven of seven patients), and TRH (seven of seven patients) and enhanced responses to GHRP plus GHRH (two of four patients) or TRH plus GHRH (six of six patients). In an in vitro dispersed cell study, the majority of patients examined also showed clear GH responses to GHRP (four of four patients), GHRH (six of six patients), and TRH (four of four patients) and an enhanced response to GHRP plus GHRH (three of three patients) or TRH plus GHRH (three of four patients). In one patient (no. 3), GHRP plus forskolin (adenylate cyclase activator), but not GHRP plus phorbol 12-myristate 13-acetate (protein kinase C activator), additively enhanced the GH response. Nordihydroguaiaretic acid (NDGA; inhibitor of arachidonic cascade) inhibited GH release induced by GHRP, TRH, GHRH, TRH plus GHRH, or GHRP plus GHRH, but did not inhibit basal GH secretion. In contrast, NDGA distinctly elevated intracellular cAMP levels in another patient (no. 7) when coadministered with GHRP, GHRH, or GHRP plus GHRH, whereas cAMP levels were not modified by single administration of GHRP and NDGA. The GH response to the combined administration of GHRP and GHRH was synergistic in this patient, but was additive in the other two patients. It is concluded that GHRP, TRH, and GHRH directly stimulate in vivo and in vitro GH release from human somatotropinomas, and GHRP and TRH mainly exert their action through activation of the phosphatidylinositol-protein kinase C pathway, whereas GHRH exerts its action through the adenylate cyclase-protein kinase A pathway. These three agents seem to release GH via the arachidonic cascade.
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PMID:Secretory mechanisms of growth hormone (GH)-releasing peptide-, GH-releasing hormone-, and thyrotropin-releasing hormone-induced GH release in patients with acromegaly. 976 68