GABA(A) receptors are believed to be heteropentamers that can be constructed from six subunit classes: alpha(1-6), beta(1-4), gamma(1-3), delta, epsilon, and pi. 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 beta 2 and beta 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 beta 3 subtlnit that mediate functional cell surface expression of this subunit compared with beta 2, which is retained within the endoplasmic reticulum. Substitution of these four amino acids-glycine 171, lysine 173, glutamate 179, and arginine 180-into the beta 2 subunit was sufficient to enable the beta 2 subunit to homo-oligomerize. The effect of this putative "assembly signal" on the production of heteromeric receptors composed of crp and pr subunits was also analyzed. This signal was not critical for the formation of receptors composed of either alpha 1 beta 2 or alpha 1 beta 3 subunits, suggesting that mutation of these residues did not disrupt subunit folding. However, this signal was important in the formation of beta gamma 2 receptors. These residues did not seem to affect the initial association of beta 2 and gamma 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 beta subunits that mediate the selective assembly of GABA(A) receptors.
|Number of pages||12|
|Journal||Journal of Neuroscience|
|Publication status||Published - 1 Aug 1999|
- GABA receptor
- Cell surface