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0026-895X/97/040714-11$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 52:714-724 (1997).

The Role of alpha 1 and alpha 6 Subtype Amino-Terminal Domains in Allosteric Regulation of gamma -Aminobutyric Acida Receptors

Janet L. Fisher, Jie Zhang, and Robert L. Macdonald

Departments of Neurology (J.L.F., J.Z., R.L.M.) and Physiology (R.L.M.), University of Michigan Medical Center, Ann Arbor, Michigan 48104-1687

The gamma -aminobutyric acidA (GABA) receptor in the mammalian central nervous system is composed of pentameric combinations of alpha 1-6, beta 1-4, gamma 1-3, delta 1, and/or epsilon 1 subunit subtypes. Although each of the different subunits influences the functional properties of gamma -aminobutyric acidA receptors (GABARs), the alpha  subunit subtypes have been shown to be important for activation of the receptor by GABA and pentobarbital and the regulation of GABARs by numerous allosteric regulators, including benzodiazepines, furosemide, zinc, and lanthanum. However, with the exception of the benzodiazepines, the alpha  subtype domain that is responsible for the action of these allosteric compounds is unknown. The alpha 1 and alpha 6 subtypes are among the most diverse of the alpha  subunit family and confer a different responsiveness of GABARs to GABA and many of the allosteric modulators. These regulatory compounds act after extracellular application and therefore likely act on extracellular GABAR sites, the largest of which is the amino-terminal extracellular domain. To determine the role of this domain in the action of these allosteric regulatory agents, we constructed chimeras of the rat alpha 1 and alpha 6 subtypes with a splice site within the first putative transmembrane domain (TM). This separated the large extracellular amino-terminal domain from the transmembrane, intracellular, and TM2-3 and carboxyl-terminal extracellular domains of the subunit. The chimeric subtypes were expressed in L929 fibroblasts along with beta 3 and gamma 2L subtypes, and their pharmacological properties were determined with whole-cell electrophysiological recording. The alpha  subtype amino-terminal extracellular domain was the primary determinant of GABA sensitivity and was responsible for the functional properties of activation by pentobarbital, sensitivity to diazepam, potentiation by lanthanum, and high affinity inhibition by furosemide. The remaining carboxyl-terminal domains influenced the GABA sensitivity and determined zinc sensitivity and low affinity inhibition by furosemide. Both domains were apparently required for inhibition by lanthanum.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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