The tyrosine kinase inhibitor genistein directly inhibits GABA(A) receptors

The protein tyrosine kinase (PTK) inhibitor genistein has been widely used to examine potential effects of tyrosine phosphorylation on neurotransmitter function. We report here that genistein inhibits GABA(A) receptors through a direct effect. Extracellular application of genistein and GABA reversibly inhibited GABA-activated currents recorded from HEK293 cells expressing rat α1β2γ2S or α1β2 receptors, even when genistein was preequilibrated in the intracellular solution. Daidzein, an analog of genistein that does not block PTK, also inhibited GABA-activated current. Coapplication of lavendustin A, a specific inhibitor of PTK, had no effect on the GABA response. Our results demonstrate that genistein has a direct inhibitory effect on GABA(A) receptors that is not mediated via inhibition of tyrosine kinase.