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  • Title: Lack of involvement of G proteins in the activation of cardiac CFTR Cl- current by genistein.
    Author: Shuba LM, McDonald TF.
    Journal: Pflugers Arch; 1999 May; 437(6):796-803. PubMed ID: 10370056.
    Abstract:
    The involvement of guanine nucleotide-binding proteins (G proteins) in the activation of cardiac adenosine 3',5'-cyclic monophosphate (cAMP)-dependent cystic fibrosis transmembrane conductance regulator (CFTR) Cl- current (ICl) by the tyrosine kinase inhibitor genistein (GST) was investigated in guinea-pig ventricular myocytes. Pertussis toxin (PTX) and intracellular application of 1 mM non-hydrolysable guanosine-5'-0-(2-thiodiphosphate) (GDPbetaS) and guanosine-5'-0-(3-thiotriphosphate) (GTPgammaS) were used to modify G protein activity, and the efficacy of the treatments determined by examining the activation of ICl by isoproterenol (ISO) and forskolin (FSK), and its inhibition by 1 microM acetylcholine (ACh). GDPbetaS inhibited ISO-activated ICl by 80-90%, but had little effect on ICl activated by different GST regimens (50 microM; 100 microM; 50 microM plus 0.1 microM FSK). GTPgammaS had little effect on the amplitude of ICl activated by 1 microM ISO, whereas it increased the amplitude of the current activated by 50 and 100 microM GST and rendered it insensitive to 1 microM ACh (inhibition of 2+/-2% versus (PTX-sensitive) inhibition of 94+/-3% in control myocytes). Unlike ICl activated by ISO in GTPgammaS-dialysed myocytes, ICl activated by GST deactivated on removal of the drug. GST (50 microM) reversibly increased ICl by nearly 50% in myocytes with Gs selectively activated by 1 microM ISO, and also reversibly increased the ICl that was persistently activated after withdrawal of ISO from GTPgammaS-dialysed myocytes. These results indicate that G proteins are not involved in the pathway between GST binding and CFTR opening, and suggest that enhanced adenylate cyclase activity in GTPgammaS-dialysed myocytes mediates the potentiated responses to GST.
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