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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 3, September, 2001 291-298

Role of Lysophosphatidylcholine in the Desensitization of beta -Adrenergic Receptors by Ca2+ Sensitization in Tracheal Smooth Muscle

Hiroaki Kume, Satoru Ito, Yasushi Ito, and Kenichi Yamaki

Second Department of Internal Medicine, School of Medicine, Nagoya University, Nagoya, Japan

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 Ca2+ 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 µM Lyso-PC markedly reduced subsequent inhibition by 0.3 µM ISO against 1 µM 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 Ca2+ by rho, a small G protein, in airway smooth muscle, and that activation of the stimulatory G protein of adenylyl cyclase, Gs, may prevent this phenomenon.

Abbreviations: arachidonic acid, AA; bisindolylmaleimide, BIS; intracellular Ca2+ concentration, [Ca2+]i; cyclic adenosine monophosphate, cAMP; cholera toxin, CTX; the stable analog of cAMP, db-cAMP; concentration of relaxant agents that produce 50% inhibition, EC50; acetoxymethyl ester of fura-2, fura 2/AM; PTX-sensitive G protein, Gi; the stimulatory G protein of adenylyl cyclase, Gs; guanidine triphosphatase, GTPase; isoproterenol, ISO; inhibition constant, Ki; lysophosphatidylcholine, Lyso-PC; methacholine, MCh; prostaglandin, PG; protein kinase, PK; phospholipase, PL; pertussis toxin, PTX.




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