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The Journal of Neuroscience, August 1, 1999, 19(15):6360-6371
Identification of Amino Acid Residues within GABAA
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
GABAA 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 acids glycine 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
GABAA receptors.
Key words:
GABA receptor; homomeric; heteromeric; assembly; benzodiazepine; cell surface
Copyright © 1999 Society for Neuroscience 0270-6474/99/19156360-12$05.00/0
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