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The Journal of Neuroscience, August 1, 1999, 19(15):6360-6371

Identification of Amino Acid Residues within GABA_A Receptor  Subunits that Mediate Both Homomeric and Heteromeric Receptor Expression

Pamela M. Taylor¹, Philip Thomas², George H. Gorrie¹, Christopher N. Connolly¹, Trevor G. Smart², and Stephen J. Moss¹

¹ The Medical Research Council Laboratory for Molecular Cell Biology and Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, and ² Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom

GABA_A receptors are believed to be heteropentamers that can be constructed from six subunit classes: (1-6), (1-4), (1-3), , , and . Given that individual neurons often express multiple receptor subunits, it is important to understand how these receptors assemble. To determine which domains of receptor subunits control assembly, we have exploited the differing capabilities of the 2 and 3 subunits to form functional cell surface homomeric receptors. Using a chimeric approach, we have identified four amino acids in the N-terminal domain of the 3 subunit that mediate functional cell surface expression of this subunit compared with 2, which is retained within the endoplasmic reticulum. Substitution of these four amino acidsglycine 171, lysine 173, glutamate 179, and arginine 180into the 2 subunit was sufficient to enable the 2 subunit to homo-oligomerize. The effect of this putative "assembly signal" on the production of heteromeric receptors composed of and subunits was also analyzed. This signal was not critical for the formation of receptors composed of either 12 or 13 subunits, suggesting that mutation of these residues did not disrupt subunit folding. However, this signal was important in the formation of 2 receptors. These residues did not seem to affect the initial association of 2 and 2 subunits but appeared to be important for the subsequent production of functional receptors. Our studies identify, for the first time, key residues within the N-terminal domains of receptor  subunits that mediate the selective assembly of GABA_A receptors.

Key words: GABA receptor; homomeric; heteromeric; assembly; benzodiazepine; cell surface

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19156360-12$05.00/0

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