Deletion of the fyn-kinase gene alters sensitivity to GABAergic drugs: dependence on beta2/beta3 GABAA receptor subunits.
Tyrosine phosphorylation can modulate GABA(A) receptor function, and deletion of the fyn-kinase gene alters GABAergic function in olfactory bulb neurons, as reported by Kitazawa, Yagi, Miyakawa, Niki, and Kawai (J Neurophysiol 1998;79:137-142). Our goal was to determine whether fyn gene deletion altered behavioral and functional actions of compounds that act on GABA(A) receptors. Such evidence might suggest a role for fyn-kinase in modulating GABA(A) receptor function, possibly via direct interactions between the kinase and receptor. Using the loss of righting reflex test, we found that null mutants were less sensitive to the hypnotic effects of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a GABA(A) receptor agonist. Subunit specificity was suggested by the observation that null mutants were also less sensitive to the hypnotic effects of etomidate, a GABAergic compound that is selective for receptors possessing beta2 and/or beta3 receptor subunits. The genotypes did not differ in sensitivity to zolpidem, an alpha1-selective GABAergic drug. GABA(A) receptor functional assays ((36)Cl(-) influx) supported our behavioral results; the actions of the GABA(A) agonists, THIP and muscimol, were reduced in the cerebellar membranes of fyn-null mutant mice. Importantly, similar results were seen with etomidate. Binding of [(3)H]flunitrazepam supported the idea that this is due to a decrease in functional GABA(A) receptor density. These data suggest that fyn-kinase may alter the function of GABA(A) receptors, perhaps via actions on beta2 and/or beta3 receptor subunits.
Boehm
Stephen L
SL
University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, 1 University Station A4800, Austin TX, 78712-0159, USA. slboehm@mail.utexas.edu
Peden
Laura
L
Harris
R Adron
RA
Blednov
Yuri A
YA
D000818:Animals; D001665:Binding Sites; D005445:Flunitrazepam / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology; D017353:Gene Deletion; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012018:Reflex; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018755:GABA Agonists; D018757:GABA Modulators; D007555:Isoxazoles; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D011963:Receptors, GABA-A; D014316:Tritium; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C015542:gaboxadol