The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABA_A receptors

Given the association of a ?2 mutation (R43Q) with epilepsy and the
reduced cell surface expression of mutant receptors, we investigated a
role for this residue in a1ß2?2 receptor assembly when present in each
subunit. Regardless of which subunit contained the mutation, mutant GABA_A
receptors assembled poorly into functional cell surface receptors. The
low level of functional expression gives rise to reduced GABA EC₅₀s
(a1(R43Q)ß2?2 and a1ß2(R43Q)?2) or reduced benzodiazepine potentiation
of GABA-evoked currents (a1ß2?2(R43Q)). We determined that a 15-residue
peptide surrounding R43 is capable of subunit binding, with a profile
that reflected the orientation of subunits in the pentameric receptor.
Subunit binding is perturbed when the R43Q mutation is present
suggesting that this residue is critical for the formation of
inter-subunit contacts at (+) interfaces of GABA_A subunits.
Rather than being excluded from receptors, ?2(R43Q) may form
non-productive subunit interactions leading to a dominant negative
effect on other receptor subtypes.