The alpha and gamma subunit-dependent effects of local anesthetics on recombinant GABA(A) receptors

Although convulsions due to local anesthetic systemic toxicity are thought to be due to inhibition of GABA(A) receptor-linked currents in the central nervous system, the mechanism of action remains unclear. We therefore exami ned the effects of local anesthetics on gamma-aminobutyric acid (GABA)-indu ced currents using recombinant GABA(A) receptors with specific combinations of subunits. Murine GABA(A) receptors were expressed by injection of cRNAs encoding each subunit into Xenopus oocytes. The effects of local anestheti cs (lidocaine, bupivacaine, procaine and tetracaine) on GABA-induced curren ts of receptors expressing different subunit combinations (alpha 1 beta 2, alpha 1 beta 2 gamma 2s. alpha 4 beta 2 gamma 2s and beta 2) were examined via the two electrode voltage clamp method. At alpha 1 beta 2, alpha 1 beta 2 gamma 3s and alpha 4 beta 2 gamma 2s GABA(A) receptors, all local anesth etics inhibited GABA-induced currents in a dose-dependent manner. The prese nce of the gamma 2s subunit resulted in a greater inhibition by all local a nesthetics, but the presence of the alpha 4 subunit resulted in less inhibi tion. At beta 2 homomeric receptors, local anesthetics directly induced an outward current similar to that of picrotoxin. These data indicated that (1 ) the alpha and gamma subunits of GABA(A) receptors modulated the inhibitor y effects of local anesthetics on GABA(A) function, and (2) local anestheti cs can activate the beta 2 subunit and may block the GABA(A) receptor chann el pore. (C) 2000 Elsevier Science B.V. All rights reserved.