Modulation of GABAA receptors by benzodiazepines and barbiturates is autonomous of PKC activation

Previous studies have suggested that activation of calcium-phospho lipid-dependent protein kinase (PKC) enhances benzodiazepine (BZD)- and pentobarbital (PB)- mediated potentiation of alpha (1)beta (1)gamma (2) GABA(A) receptors (GABA(A)-Rs). To delineate the underlying mechanism(s). voltage-clamp recordings were performed on recombinant alpha (1)beta (1)gamma (2) GABA(A) receptors functionally expressed in Xenopus laevis oocytes. GABA(A)-Rs were tested for their sensitivity to diazepam and PB before and after incubation in phorbol 12-myristate 13-acetate (PMA). PMA (25 nM) significantly attenuated the GABA(A) current (p<0.05, n=12-19) up to 90%. PMA treatment. however, did not alter the sensitivity to diazepam or pentobarbital. Similar results were obatined with recombinant <alpha>(1)beta (2)gamma (2) GABA receptors. These data suggest that PKC activation does not alter the allosteric modulation of GABA(A)-Rs by benzodiazepines and barbiturates and is consistent with the observation from other studies in oocytes that PMA decreases the amplitude of the GABA-activated currents via receptor internalization rather than modification of receptor kinetics. (C) 2001 Elsevier Science Ltd. All rights reserved.