Protein tyrosine kinase inhibitors reduce high-voltage activating calcium currents in CA1 pyramidal neurones from rat hippocampal slices

We have investigated the effects of protein tyrosine kinases (PTKs) inhibit ors on high-threshold voltage activating (HVA) calcium currents in CAl pyra midal neurones, whole-cell patch-clamp recorded from rat hippocampal slices . Genistein (100 mu M) and tyrphostin B42 (100 mu M), two PTKs inhibitors, reduced the steady-state barium current (I-Ba). On the other hand, daidzein and genistin (100 mu M), two inactive analogues of genistein, had no effec t on I-Ba amplitude. The inhibition induced by genistein was more pronounce d at negative potentials. In order to characterize the calcium channels sub types inhibited by PTKs inhibitors, we examined the effect of genistein in the presence of different calcium channel blockers. When L-type calcium cha nnels were blocked by nifedipine, genistein induced a strong inhibition of the nifedipine-resistant I-Ba, suggesting an effect on non-L-type channels. Genistein did not antagonize the depressant effect of omega-Conotoxin-GVIA , a selective N-type calcium channel blocker, suggesting that N-type channe ls were not blocked by genistein. omega-Conotoxin-MVIIC (3-10 mu M), a sele ctive P/Q-type calcium channel blocker, greatly antagonized the depressant effect of genistein. Our results suggest that PTKs inhibitors reduce P-/Q-t ype, but not L- or N-types calcium currents in neurones of the CNS. The pos sible modulation of calcium channels by endogenous PTKs is discussed. (C) 1 999 Published by Elsevier Science B.V. All rights reserved.