Tyrosine kinase inhibitors enhance a Ca(2+)-activated K+ current (IAHP) and reduce IAHP suppression by a metabotropic glutamate receptor agonist in rat dentate granule neurones.
1. Activation of metabotropic glutamate receptors (mGluRs) inhibits a transient Ca(2+)-activated K+ current (IAHP) 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 IAHP by the selective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). Inhibition of IAHP by 5-HT was unaffected. The PTK blockers by themselves doubled the duration of IAHP suggesting that there exists a tonic inhibitory influence on IAHP that is reduced by PTK antagonists. 3. Inclusion of EGTA (1 mM) in the patch pipette also potentiated the IAHP and reduced the inhibitory action of ACPD on IAHP, 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 IAHP.
Abdul-Ghani
M A
MA
MRC Nerve Cell and Synapse Group, Faculty of Pharmacy, Toronto Hospital Research Institute, Ontario, Canada.
Valiante
T A
TA
Carlen
P L
PL
Pennefather
P S
PS
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D019311:Staurosporine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007529:Isoflavones; D009498:Neurotoxins; D015221:Potassium Channels; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D000262:Adenylyl Cyclases; D019311:Staurosporine; D002118:Calcium