TYROSINE KINASE INHIBITORS ENHANCE A CA2-ACTIVATED K+ CURRENT (I-AHP)AND REDUCE I-AHP SUPPRESSION BY A METABOTROPIC GLUTAMATE-RECEPTOR AGONIST IN RAT DENTATE GRANULE NEURONS()

1. Activation of metabotropic glutamate receptors (mGluRs) inhibits a transient Ca2+-activated K+ current (I-AHP) responsible fur the slow a fter-hyperpolarization that follows depolarizations of dentate granule neurones in rat hippocampal brain slices. Here we show for the first time that this physiological consequence of mGluR stimulation is selec tively attenuated by blockers of protein tyrosine kinases (PTKs). 2. S everal distinct types of PTK blockers, including genistein, tyrphostin -B42 and lavendustin-A, reduced the inhibition of I-AHP by the selecti ve mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (AC PD). Inhibition of I-AHP by 5-HT was unaffected. The PTK blockers by t hemselves doubled the duration of I-AHP suggesting that there exists a tonic inhibitory influence on I-AHP that is reduced by PTK antagonist s. 3. Inclusion of EGTA (1 mM) in the patch pipette also potentiated t he I-AHP and reduced the inhibitory action of ACPD on I-AHP, consisten t with the observation of others that chelation Ca2+ prevents protein tyrosine phosphorylation induced by ACPD, 4. The propose that mGluR-in itiated inositol 1,4,5-trisphosphate (InsP(3)) production mobilizes in tracellular Ca2+ and leads to increased protein tyrosine phosphorylati on which in turn leads to inhibition of I-AHP.