The promiscuous role of the epsilon subunit in GABAA receptor biogenesis

The formation of α1β2γ2ε receptors suggests that the ε subunit does not displace the single γ2 subunit in α1β2γ2 receptors. Thus, ε must replace α and/or β subunit(s) if the pentameric receptor structure is to be preserved. To assess the potential for which subunit is replaced in αβε and αβγε receptors we analyzed the assembly and functional expression of the ε subunit with respect to α1, β2 and γ2 subunits. Using concatenated subunits, we have determined that ε is capable of substituting for either (but not both) of the α subunits, one of the β subunits, and possibly the γ2 subunit. However, the most likely sites at which the ε subunit may contribute to receptor function appears to be at position 1 (replaces α1) in αβγε (ɛ–β2–α1–β2–γ2) receptors, or at position 4 (replaces β2) in αβε (α1–β2–α1–ɛ–β2) receptors. In both cases, it appears that only a single GABA binding site is present.