M. Sugimoto et al., The alpha and gamma subunit-dependent effects of local anesthetics on recombinant GABA(A) receptors, EUR J PHARM, 401(3), 2000, pp. 329-337
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.