The calcineurin inhibitor cyclosporin A-cyclophilin A complex reduces desensitization of GABAA-mediated responses in acutely dissociated rat hippocampal neurons.
The effects of the selective inhibitor of calcineurin, cyclosporin A-cyclophilin A (CC) complex on the desensitization kinetics of GABAA receptors was studied in acutely dissociated hippocampal neurons, using the patch clamp technique in the whole cell configuration. In control conditions, the decay of GABA-evoked current could be fitted by a biexponential function having time constants of 0.65 +/- 0.24 s and 3.75 +/- 2 s. The plateau to peak ratio was 0.087 +/- 0.034. Recovery from desensitization was obtained in more than 2 min. In cells dialyzed with the CC complex, the decay of the currents could be fitted with the sum of two exponentials having time constants similar to controls (0.81 +/- 0.47 s and 3.62 +/- 2.1 s), but the percentage of the fast component was smaller. The plateau to peak ratio was significantly larger than control (0.185 +/- 0.07). With CC complex, recovery from desensitization was completed in almost 30 s. The cyclosporin A derivative PSC 833, which does not inhibit calcineurin, did not affect desensitization kinetics. These results suggest that phosphatase 2B regulates desensitization of GABAA receptors.
Biophysics Sector, International School for Advanced Studies (SISSA), Trieste, Italy.
M
M
Martina
J W
JW
Mozrzymas
H W
HW
Boddeke
E
E
Cherubini
D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007700:Kinetics; D009474:Neurons / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012680:Sensitivity and Specificity; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D003524:Cyclosporins; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; C070272:valspodar