TY - JOUR T1 - Direct Block of Voltage-Sensitive Sodium Channels by Genistein, A Tyrosine Kinase Inhibitor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 521 LP - 526 VL - 280 IS - 2 AU - Christophe Paillart AU - Edmond Carlier AU - Denis Guedin AU - Bénédicte Dargent AU - François Couraud Y1 - 1997/02/01 UR - http://jpet.aspetjournals.org/content/280/2/521.abstract N2 - Genistein, an isoflavone inhibitor of tyrosine-specific protein kinases, was shown to specifically block the22Na+ influx through voltage-sensitive Na+ channels in cultured rat brain neurons, whereas other tyrosine kinase antagonists such as lavendustin A, compound 5, tyrphostin A47 and an erbstatin analog were inactive at concentrations known to block kinase activity in other neuronal systems. Dose-response curves for genistein indicated a half-maximum effect at 60 μM. Daidzein, an inactive analog of genistein, had a similar inhibitory effect on the 22Na+ influx with a half-maximum effect at 195 μM. The time course of genistein action was rapid, because maximum effect on22Na+ influx was obtained in less than 20 s at 100 μM. Analysis of Na+ currents by the whole-cell recording technique showed that 20 μM genistein reduced the sodium current and shifted the voltage dependence of both activation and inactivation curves. No competition with [3H]saxitoxin binding was observed, whereas the binding of [3H]batrachotoxinin A 20-α-benzoate to rat brain synaptosomal membranes was partially inhibited, which suggested a direct or allosteric interaction with neurotoxin binding site 2. These data taken together clearly indicate that the inhibition of voltage-sensitive sodium channels by genistein is not mediated by tyrosine kinase inhibition. The American Society for Pharmacology and Experimental Therapeutics ER -