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Volume 17, Number 2, Issue of January 15, 1997 pp. 625-634
Copyright ©1997 Society for Neuroscience

Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABA_A Receptor

Received Aug. 15, 1996; revised Oct. 31, 1996; accepted Nov. 15, 1996.

Shinya Ueno¹, John Bracamontes¹, Chuck Zorumski², David S. Weiss³, and Joe Henry Steinbach¹

Departments of ¹ Anesthesiology and ² Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, and ³ University of Alabama at Birmingham, Neurobiology Research Center and Department of Physiology and Biophysics, Birmingham, Alabama 35294-0021

Anesthetic drugs are known to interact with GABA_A receptors, both to potentiate the effects of low concentrations of GABA and to directly gate open the ion channel in the absence of GABA; however, the site(s) involved in direct gating by these drugs is not known. We have studied the ability of alphaxalone (an anesthetic steroid) and pentobarbital (an anesthetic barbiturate) to directly activate recombinant GABA_A receptors containing the 1, 2, and 2L subunits. Steroid gating was not affected when either of two mutated 2 subunits [2(Y157S) and 2(Y205S)] are incorporated into the receptors, although these subunits greatly reduce the affinity of GABA binding. These observations indicate that steroid binding and subsequent channel gating do not require these particular residues, as already shown for barbiturates. Bicuculline or gabazine (two competitive antagonists of GABA binding) reduced the currents elicited by alphaxalone and pentobarbital from wild-type GABA_A receptors; however, gabazine produced only a partial block of responses to pentobarbital or alphaxalone, and bicuculline only partially blocked responses to pentobarbital. These observations indicate that the blockers do not compete with alphaxalone or pentobarbital for a single class of sites on the GABA_A receptor. Finally, at receptors containing 12(Y157S)2L subunits, both bicuculline and gabazine showed weak agonist activity and actually potentiated responses to alphaxalone. These observations indicate that the blocking drugs can produce allosteric changes in GABA_A receptors, at least those containing this mutated 2 subunit. We conclude that the sites for binding steroids and barbiturates do not overlap with the GABA-binding site. Furthermore, neither gabazine nor bicuculline competes for binding at the steroid or barbiturate sites. The data are consistent with a model in which both gabazine and bicuculline act as allosteric inhibitors of channel opening for the GABA_A receptor after binding to the GABA-binding site.

Key words: GABA_A receptor; GABA; neurosteroids; bicuculline; inverse agonist; anesthetics; allosteric inhibitor

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