HALOTHANE ACTS AS A PARTIAL AGONIST OF THE ALPHA-6-BETA-2-GAMMA-2S GABA(A) RECEPTOR

Whole-cell patch clamp recording was performed on human embryonic kidn ey 293 cells stably transfected with rat cDNAs for the alpha 6, beta 2 , and gamma 2S subunits of the GABA(A) receptor, The volatile anesthet ic halothane directly activated a current in the absence of the ligand gamma-aminobutyric acid (GABA), Both the current amplitude and the ra te of desensitization increased in a dose-dependent manner with an EC( 50) of 1.0+/-0.2 mM and a Hill coefficient (n(h)) of 1.5+/-0.1, The EC (50) and n(h) for GABA to activate the receptor were 1.0+/-0.3 mu M an d 1.4+/-0.2, respectively, The peak amplitude of the halothane-activat ed current was about 4% of the maximal GABA response, which was not ch anged when the concentration of Ca2+ in the external solution was decr eased from 2 mM to 0.2 mM. The reversal potential of both halothane- a nd GABA-activated currents changed with the external Cl- concentration as predicted by the Nernst equation for chloride ions, The halothane- and GABA-activated currents were blocked by both the noncompetitive G ABA(A) receptor antagonist picrotoxin and the competitive GABA(A) rece ptor antagonist bicuculline. Schild plots revealed that the K(i)s for bicuculline to competitively antagonize the currents activated by halo thane and GABA are similar (0.69 and 0.72 mu M, respectively), These r esults indicate that halothane activates the alpha 6 beta 2 gamma 2S G ABA(A) receptor to induce a current similar to the GABA-induced curren t.