The α and γ subunit-dependent effects of local anesthetics on recombinant GABA A receptors

Abstract

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 examined the effects of local anesthetics on γ-aminobutyric acid (GABA)-induced 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 anesthetics (lidocaine, bupivacaine, procaine and tetracaine) on GABA-induced currents of receptors expressing different subunit combinations (α1β2, α1β2γ2s, α4β2γ2s and β2) were examined via the two electrode voltage clamp method. At α1β2, α1β2γ2s and α4β2γ2s GABA A receptors, all local anesthetics inhibited GABA-induced currents in a dose-dependent manner. The presence of the γ2s subunit resulted in a greater inhibition by all local anesthetics, but the presence of the α4 subunit resulted in less inhibition. At β2 homomeric receptors, local anesthetics directly induced an outward current similar to that of picrotoxin. These data indicated that (1) the α and γ subunits of GABA A receptors modulated the inhibitory effects of local anesthetics on GABA A function, and (2) local anesthetics can activate the β2 subunit and may block the GABA A receptor channel pore.