title: Cocaine inhibition of GABA(A) current: role of dephosphorylation.
abstract: Acute cocaine toxicity is frequently associated with seizures. The mechanisms underlying the convulsant effect of cocaine are not well understood. Previously, we have shown that cocaine depresses whole-cell current evoked by gamma-aminobutyric acid (GABA) in hippocampal neurons freshly isolated from rats. Cocaine's effect was voltage-independent and concentration-dependent. In the present study, using whole-cell patch-clamp recording on rat neurons freshly isolated from hippocampus, we examined the intracellular mechanisms involved in cocaine's action. Increasing intracellular Ca(2+) concentration ([Ca]i) from 0.01 to 5 microM strongly increased the depressant effect of cocaine. By contrast, 1-[N, O-bis (5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a specific antagonist of Ca/calmodulin-dependent protein kinase (CaMKII), attenuated or enhanced cocaine's action in different neurons: in three out of nine neurons dialysed with 5 microM KN-62,1 mM cocaine depressed GABA current by only 33%, but in another three out of nine neurons, cocaine depressed GABA current by as much as 83%. Chelerythrine (a specific CaCa(2+)/phospholipid-dependent protein kinase C [PKC] antagonist) had minimal effect on cocaine's action. We suggest that cocaine induces an increase in [Ca]i, which stimulates phosphatase activity and thus leads to dephosphorylation of GABA receptors. This dephosphorylation-mediated disinhibitory action may play a role in cocaine-induced convulsant states.
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Newark, New Jersey 07103-2714, USA. ye@umdnj.edu
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Ye
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010744:Phosphoric Monoester Hydrolases; D003042:Cocaine; D002118:Calcium