α/β-Hydrolase domain-containing 6 (ABHD6) accelerates the desensitization and deactivation of TARP γ-2-containing AMPA receptors

Abstract

AMPA receptors (AMPARs) mediate most of the fast excitatory synaptic transmission in mammalian brain. Their efficacy in responding to presynaptic glutamate release depends on their kinetics, which are determined by AMPARs and their auxiliary subunit composition. α/β-Hydrolase domain-containing 6 (ABHD6) is an AMPAR auxiliary subunit that has been shown to negatively regulate the surface delivery of AMPARs and AMPAR-mediated currents. Overexpression of ABHD6 decreased the rising slope and increased the decay τ of mEPSCs. However, whether ABHD6 is involved in regulating AMPAR kinetics remains unclear. Here, we found that ABHD6 per se had no effects on the gating kinetics of GluA1 and GluA2(Q) containing homomeric receptors. However, in the presence of the auxiliary subunit TARP γ-2, ABHD6 accelerated the deactivation and desensitization of either GluA1 and GluA2(Q) containing homomeric receptors independent of their splicing isoforms (flip and flop) and the editing isoforms of GluA2 (R or G at position 764), except the deactivation of GluA2(Q)i-G isoform. Besides, the recovery from desensitization of GluA1 with flip splicing isoform was slowed by the co-expression of ABHD6 in the presence of TARP γ-2. Furthermore, the ABHD6 accelerated the deactivation and desensitization of GluA1i/GluA2(R)i-G heteromeric receptors in the presence of TARP γ-2. Therefore, these results demonstrate that ABHD6 regulates AMPAR gating kinetics in a TARP γ-2-dependent manner.