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Volume 17, Number 13, Issue of July 1, 1997 pp. 5062-5069
Copyright ©1997 Society for Neuroscience

Modulation of GABA_A Receptor Function by Tyrosine Phosphorylation of  Subunits

Received Dec. 19, 1996; revised April 16, 1997; accepted April 21, 1997.

Qi Wan^{1, 2}, Heng Ye Man^{1, 2}, Jodi Braunton^{1, 2}, Wei Wang^{1, 2}, M. W. Salter^{2, 3}, L. Becker¹, and Yu Tian Wang^{1, 2}

Divisions of ¹ Pathology and ² Neuroscience, Research Institute of Hospital for Sick Children, and Departments of ¹ Pathology and ³ Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada

Protein tyrosine phosphorylation is a key event in diverse intracellular signaling pathways and has been implicated in modification of neuronal functioning. We investigated the role of tyrosine phosphorylation in regulating type A GABA (GABA_A) receptors in cultured CNS neurons. Extracellular application of genistein (50 µM), a membrane-permeable inhibitor of protein tyrosine kinases (PTKs), produced a reversible reduction in the amplitude of GABA_A receptor-mediated whole-cell currents, and this effect was not reproduced by daidzein (50 µM), an inactive analog of genistein. In contrast, intracellular application of the PTK pp60^c-src (30 U/ml) resulted in a progressive increase in current amplitude, and this potentiation was prevented by pretreatment of the neurons with genistein. Immunoprecipitation and immunoblotting of cultured neuronal homogenates indicated that the 2/3 subunit(s) of the GABA_A receptor are tyrosine phosphorylated in situ. Moreover, genistein (50 µM) was found to be capable of decreasing GABA_A currents in human embryonic kidney 293 cells transiently expressing functional GABA_A receptors containing the 2 subunit. Thus, the present work provides the first evidence that native GABA_A receptors are phosphorylated and modulated in situ by endogenous PTKs in cultured CNS neurons and that phosphorylation of the  subunits may be sufficient to support such a modulation. Given the prominent role of GABA_A receptors in mediating many brain functions and dysfunctions, modulation of these receptors by PTKs may be important in a wide range of physiological and pathological processes in the CNS.

Key words: GABA_A receptor; protein tyrosine phosphorylation; protein tyrosine kinase; cultured neurons; recombinant GABA_A receptor; HEK 293 cell

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