Role of lysophosphatidylcholine in the desensitization of beta-adrenergic receptors by Ca(2+) sensitization in tracheal smooth muscle.
Lysophosphatidylcholine (Lyso-PC) is generally considered to promote tissue inflammation. To determine the involvement of exogenous Lyso-PC in the beta-adrenergic desensitization by phospholipase A2, we examined the inhibitory effects of isoproterenol (ISO) on tension and intracellular Ca(2+) concentration by methacholine (MCh) after continuous exposure to Lyso-PC in guinea-pig tracheal smooth muscle, using isometric tension recordings and fura-2 signal (F340/F380 ratio). Pre- exposure to 10 microM Lyso-PC markedly reduced subsequent inhibition by 0.3 microM ISO against 1 microM MCh-induced contraction in a time-dependent manner. In contrast, values of percent F340/F380 ratio for MCh with ISO were not affected after exposure to Lyso-PC. In the presence of Y-27632, a selective rho-kinase inhibitor, a reduction in subsequent relaxation by ISO after exposure to Lyso-PC was inhibited in a concentration-dependent manner. Preincubation with cholera toxin also inhibited reduced responsiveness to ISO by Lyso-PC. Pre-exposure to Lyso-PC did not attenuate subsequent relaxation by agents that bypass beta-adrenergic receptors. These results indicate that continuous exposure to Lyso-PC may cause homologous desensitization of beta-adrenergic receptors via an augmentation in sensitivity to Ca(2+) by rho, a small G protein, in airway smooth muscle, and that activation of the stimulatory G protein of adenylyl cyclase, G(s), may prevent this phenomenon.
Kume
H
H
Second Department of Internal Medicine, School of Medicine, Nagoya University, Nagoya, Japan. hkume@tsuru.med.nagoya-u.ac.jp
Ito
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S
Ito
Y
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Yamaki
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D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D016210:Methacholine Chloride / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013806:Theophylline / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists; D000577:Amides; D004791:Enzyme Inhibitors; D007211:Indoles; D008244:Lysophosphatidylcholines; D008301:Maleimides; D018721:Muscarinic Agonists; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D016210:Methacholine Chloride; C108830:Y 27632; D005576:Colforsin; D003994:Bucladesine; D002772:Cholera Toxin; D013806:Theophylline; D020741:rho GTP-Binding Proteins; D015232:Dinoprostone; D007545:Isoproterenol; C088060:bisindolylmaleimide; D002118:Calcium