Structural Determinants of Fast Desensitization and Desensitization–Deactivation Coupling in GABAAReceptors

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Abstract
Fast IPSCs in the brain are predominantly caused by presynaptic release of GABA that activates GABAAreceptor (GABAAR) channels. The IPSCs are shaped by the gating and desensitization properties of postsynaptic GABAARs. Specifically, fast desensitization has been suggested to decrease IPSC amplitude and to increase IPSC duration by slowing deactivation; however, the mechanisms underlying desensitization, deactivation, and their coupling are poorly understood. Consistent with this suggestion, α1β3γ2L GABAARs desensitize with a prominent fast phase and deactivate slowly, whereas α1β3δ GABAARs desensitize without a fast phase and deactivate rapidly. Using the concentration-jump technique applied to excised patches, we studied GABAARs containing chimeras or exchange mutants between δ and γ2L subunits to gain insight into the structural bases for fast desensitization and its coupling to deactivation. We demonstrated that the N terminus and two adjacent residues (V233, Y234) in the first transmembrane domain (TM1) of the δ subunit were both required to abolish fast desensitization. Additionally, these residues in TM1 of the γ2L subunit (Y235, F236) were critical for desensitized states to prolong deactivation after removal of GABA, because mutations resulted in accelerated deactivation despite unaltered desensitization time course. Interestingly, control of desensitization and deactivation was independent of the identity (γ2L or δ subunit sequence) of TM2, indicating that structures related to the putative channel gate may play a less direct role in desensitization than previously suggested.