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 neurones

1. Activation of metabotropic glutamate receptors (mGluRs) inhibits a transient Ca²⁺-activated K⁺ current (I(AHP)) responsible for the slow after-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 selectively attenuated by blockers of protein tyrosine kinases (PTKs). 2. Several distinct types of PTK blockers, including genistein, tyrphostin-B42 and lavendustin-A, reduced the inhibition of I(AHP) by the selective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). Inhibition of I(AHP) by 5-HT was unaffected. The PTK blockers by themselves doubled the duration of I(AHP) suggesting that there exists a tonic inhibitory influence on I(AHP) that is reduced by PTK antagonists. 3. Inclusion of EGTA (1 mM) in the patch pipette also potentiated the I(AHP) and reduced the inhibitory action of ACPD on I(AHP), consistent with the observation of others that chelation of intracellular Ca²⁺ prevents protein tyrosine phosphorylation induced by ACPD. 4. We propose that mGluR-initiated inositol 1,4,5-trisphosphate (InsP₃) production mobilizes intracellular Ca²⁺ and leads to increased protein tyrosine phosphorylation which in turn leads to inhibition of I(AHP).