Vol. 61, Issue 6, 1322-1328, June 2002

Amiloride Inhibition of -Aminobutyric Acid_A Receptors Depends upon the  Subunit Subtype

Janet L. Fisher

Department of Pharmacology and Physiology, University of South Carolina School of Medicine, Columbia, South Carolina

-Aminobutyric acid_A (GABA_A) receptors (GABARs) are responsible for most fast inhibitory neurotransmission in the mammalian brain. The GABARs contain several allosteric modulatory sites, many of which are useful clinically. The activity of most of these modulators depends upon the subunit composition of the receptor. The diuretic amiloride was previously reported to inhibit GABARs in frog sensory neurons. We measured its effects on recombinant GABARs to determine its mechanism of action at mammalian receptors and to examine the effect of subunit composition. Amiloride acted primarily as a competitive antagonist, reducing the sensitivity of the receptor to GABA without affecting the maximal current amplitude. Receptors containing an 6 subunit were about 10-fold more sensitive to amiloride than those containing other  subunits. In contrast, the identity of the  or  subtype had little effect on amiloride sensitivity. Although several other modulators have specific effects at 6-containing receptors, amiloride is the first inhibitor to be reported with no additional dependence on the identity of the  or  subunit. Therefore, it probably represents a unique modulatory site on the GABAR, which could be useful for developing drugs targeting these receptors. The selective activity of amiloride could also be helpful for isolating the contribution of receptors composed of 6 subtypes in heterogeneous native GABAR populations.