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J. Biol. Chem., Vol. 278, Issue 7, 4747-4755, February 14, 2003

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GABA_A Receptor Composition Is Determined by Distinct Assembly Signals within  and  Subunits^*

Karen Bollan, Dale King, Laura A. Robertson, Kenneth Brown, Pamela M. Taylor^§, Stephen J. Moss^§, and Christopher N. Connolly^¶

From the  Department of Pharmacology and Neuroscience, Ninewells Medical School, University of Dundee, Dundee DD1 9SY, Scotland and ^§ Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gordon St., London WC1E 6BT, United Kingdom

Key to understanding how receptor diversity is achieved and controlled is the identification of selective assembly signals capable of distinguishing between other subunit partners. We have identified that the 1-3 subunits exhibit distinct assembly capabilities with the 2L subunit. Similarly, analysis of an assembly box in 1-(57-68) has revealed an absolute requirement for this region in the assembly of receptors. Furthermore, a selective requirement for a single amino acid (Arg-66), previously shown to be essential for the formation of the low affinity GABA binding site, is observed. This residue is critical for the assembly of 12 but not 11 or 13 receptors. We have confirmed the ability of the previously identified GKER signal in 3 to direct the assembly of receptors. The GKER signal is also involved in driving assembly with the 1 subunit, conferring the ability to assemble with 1^R66A on the 2 subunit. Although this signal is sufficient to permit the formation of 22 receptors, it is not necessary for 32 receptor formation, suggesting the existence of alternative assembly signals. These findings support the belief that GABA_A receptor assembly occurs via defined pathways to limit the receptor diversity.

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