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Vol. 57, Issue 5, 875-882, May 2000

Mutating the Highly Conserved Second Membrane-Spanning Region 9' Leucine Residue in the alpha 1 or beta 1 Subunit Produces Subunit-Specific Changes in the Function of Human alpha 1beta 1 gamma -Aminobutyric AcidA Receptors

Julie E. Dalziel,1 Graeme B. Cox, Peter W. Gage, and Bryndis Birnir2

Membrane Biology Program, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia

The properties of the human alpha 1beta 1 gamma -aminobutyric acid (GABA)A receptors were investigated after mutation of a highly conserved leucine residue at the 9' position in the second membrane-spanning region (TM2). The role of this residue in alpha 1 and beta 1 subunits was examined by mutating the 9' leucine to phenylalanine, tyrosine, or alanine. The mutations were in either the alpha 1 subunit (alpha *beta ), the beta 1 subunit (alpha beta *), or in both subunits (alpha *beta *), and the receptors were expressed in Sf9 cells. Our results show that the rate of desensitization is increased as the size and hydrophobicity of the 9' residue in the alpha 1 subunit is increased: Y, F > L > A, T. Mutation of L9' in only the beta 1 subunit (alpha beta *) to either phenylalanine or tyrosine increased the EC50 value for GABA at least 100 times, but the EC50 was unchanged in alpha beta * alanine mutants. In the 9' alpha 1 mutants (alpha *beta , alpha *beta *) the GABA EC50 was minimally affected. In alpha *beta and alpha *beta *, but not alpha beta *, the peak currents evoked by millimolar concentrations of GABA were greatly reduced. The reduction in currents could only be partially accounted for by decreased expression of the receptors These findings suggest different roles for the two types of subunits in GABA activation and later desensitization of alpha 1beta 1 receptors. In addition, an increase in the resting membrane conductance was recorded in alanine but not in phenylalanine and tyrosine mutants, indicating that the side chain size at the 9' position is a major determinant of current flow in the closed conformation.

1 Present address: Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, CA.

2 Present address: Department of Cell and Molecular Physiology, Institute of Physiological Sciences, Lund University, Lund S-223 62, Sweden.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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