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)

Decreased airway relaxation to beta-adrenoceptor stimulation has been hypothesized as a potential mechanism leading to enhanced bronchoconstrictor responsiveness in asthma. In addressing potential mechanisms underlying this phenomenon, the relative contributions of beta-adrenoceptor-coupled transmembrane signaling mechanisms were examined in isolated rabbit tracheal smooth muscle (TSM) passively sensitized with serum from atopic asthmatic patients and in TSM comparably exposed to non-atopic (control) human serum. During half-maximal isometric contraction of the tissues with acetylcholine, relative to control TSM, the sensitized tissues exhibited significant attenuation of both their maximal relaxation (Rmax) and sensitivity (i.e., -log 50% Rmax) to cumulative administration of isoproterenol (P < 0.001) or prostaglandin (PG)E2 (P < 0.001). In contrast, the relaxation responses to forskolin, a diterpene that directly activates adenylate cyclase, were similar in both tissue groups. Extended studies demonstrated that the attenuated relaxation to isoproterenol and PGE2 in sensitized TSM was 1) ablated by pretreatment with the muscarinic M2-receptor antagonists methoctramine (10(-6) M) or gallamine (10(-4) M); 2) also inhibited by pretreatment with pertussis toxin (100 ng/ml), which ADP ribosylates the inhibitory G protein (G(i)) negatively coupled to adenylate cyclase activation; and 3) associated with diminished adenosine 3',5'-cyclic monophosphate accumulation in response to isoproterenol administration. Moreover, based on Western immunoblot analysis, we found that G(i) protein expression was increased in membrane fractions from sensitized TSM, related to enhanced expression of the G(i) alpha 3 subunit. Collectively, these observations provide new evidence that the impaired beta-adrenoceptor-mediated relaxation in atopic sensitized airways is associated with increased muscarinic M2 receptor/G(i) protein-coupled expression and function.
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PMID:Mechanism of impaired beta-adrenoceptor responsiveness in atopic sensitized airway smooth muscle. 749 84

Pretreatment of the field-stimulated rabbit isolated vas deferens for 30 min with LiCl (2 x 10(-2) and 4 x 10(-2) M) attenuated the inhibition of neurogenic twitch contractions due to muscarinic M1 receptor stimulation by 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343), and enhanced the muscarinic M2 receptor-mediated potentiation of contractions evoked by carbachol. When the tissues were preincubated for 5 min with the adenylate cyclase activator, forskolin (3 x 10(-8)-3 x 10(-7) M), the response to carbachol was attenuated whereas that to 4-Cl-McN-A-343 remained unchanged. 1,9-Dideoxy-forskolin (3 x 10(-7) and 10(-6) M), which fails to activate cyclase, did not abolish the carbachol effect. In addition, desensitization of the response to 4-Cl-McN-A-343 but not to carbachol occurred in preparations incubated for 90 min with the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA, 3 x 10(-8)-3 x 10(-7) M), whereas its inactive 4 alpha-stereoisomer (4 alpha-PMA, 3 x 10(-7) M) was without effect. In unstimulated preparations, LiCl, forskolin and PMA did not impair contractions due to exogenous ATP (10(-3) M). These findings are consistent with the hypothesis that, in rabbit vas deferens, inhibitory muscarinic M1 receptors stimulate LiCl-sensitive phosphatidylinositol turnover (IP3 pathway) involving protein kinase C, whilst excitatory muscarinic M2 receptors are coupled to inhibition of adenylate cyclase, resulting in reduced levels of cyclic AMP.
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PMID:Pathways involved in muscarinic M1 and M2 receptor stimulation in rabbit vas deferens. 752 12

Over the last decade, several lines of evidence have shown that both muscarinic M2 and M3 receptors are postjunctionally expressed in many smooth muscles, including the gastrointestinal tract. Although in vitro data suggests that both receptors are functional in that they inhibit adenylate cyclase activity and activate non-selective cation channels, few studies support a role in vivo. Thus, data from procedures that ablate the signaling pathway of the muscarinic M2 receptor, including receptor antagonism, pertussis toxin pretreatment reveal little effect on gastrointestinal smooth muscle responsiveness to muscarinic agonists. Recently, information from knockout mice, lacking either M2 or M3 receptor, indicate reveal a role for both subtypes. However, the contribution of the M2 receptor appears greater in the ileum than in the urinary bladder. Therapeutically, non-selective, as well as selective M3 receptor antagonists are being clinically studied, although it remains to be shown which is the optimal approach to disorders of smooth muscle motility.
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PMID:Muscarinic receptors and gastrointestinal tract smooth muscle function. 1139 28