Tyrosine Kinase-Independent Extracellular Action of Genistein on the CFTR Cl- Channel in Guinea Pig Ventricular Myocytes and CFTR-Transfected Mouse Fibroblasts.

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  • ZHOU Shi-Sheng
    Department of Cellular and Molecular Physiology, National Institute for Physiological Sciences Present address: Department of Physiology, The Fourth Military Medical University
  • HAZAMA Akihiro
    Department of Cellular and Molecular Physiology, National Institute for Physiological Sciences
  • OKADA Yasunobu
    Department of Cellular and Molecular Physiology, National Institute for Physiological Sciences

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  • Tyrosine Kinase-Independent Extracellul

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Abstract

The effects of genistein, a protein tyrosine kinase inhibitor, on the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel were studied in guinea pig ventricular myocytes and in NIH3T3 mouse fibroblasts stably transfected with CFTR cDNA by the whole-cell patch-clamp technique. Genistein did not activate whole-cell Cl- currents when applied to the intracellular (pipette) solution. In contrast, when applied to the extracellular solution, genistein alone promptly activated the Cl- current in a fully reversible manner. Also, extracellular genistein reversibly potentiated the forskolin-activated Cl- current. However, both basal and forskolin-activated Cl- currents were not affected by other protein tyrosine kinase inhibitors, including herbimycin A, lavendustin A, tyrphostin 21, tyrphostin 47, and tyrphostin 51. A nonspecific inhibitor of protein phosphatases, orthovanadate, had no effect on the genistein-induced activation of CFTR. Pretreatment with a protein kinase inhibitor, either H-89 or H-7, or with an adenylate cyclase inhibitor, SQ 22536, also had no effect on the genistein-induced response. Thus, it is concluded that genistein alone activates CFTR by a protein tyrosine kinase-independent and protein phosphatase-independent mechanism from the extracellular side, but not from the intracellular side.

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