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Their efficacy in responding to presynaptic glutamate release depends on their kinetics, which are determined by AMPARs and their auxiliary subunit composition. \u03b1\/\u03b2-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 has been shown to decrease the rising slope and increase the decay \u03c4 of mEPSCs. However, whether ABHD6 is involved in regulating AMPAR kinetics remains unclear. Here, we found that ABHD6 itself had no effect on the gating kinetics of GluA1 and GluA2(Q) containing homomeric receptors. However, in the presence of the auxiliary subunit TARP \u03b3-2, ABHD6 accelerated the deactivation and desensitization of both 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 for 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 \u03b3-2. Furthermore, ABHD6 accelerated the deactivation and desensitization of GluA1i\/GluA2(R)i-G and GluA2(R)i-G\/GluA3(R)i heteromeric receptors in the presence of TARP \u03b3-2. We also found that ABHD6-knockout neurons displayed slower deactivation and desensitization. Therefore, these results demonstrate that ABHD6 regulates AMPAR gating kinetics in a TARP \u03b3-2-dependent manner.<\/jats:p>","DOI":"10.7554\/elife.99623","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T08:25:34Z","timestamp":1725956734000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.99623","source":"Crossref","is-referenced-by-count":0,"title":["\u03b1\/\u03b2-Hydrolase domain-containing 6 (ABHD6) accelerates the desensitization and deactivation of TARP \u03b3-2-containing AMPA receptors"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5080-2583","authenticated-orcid":true,"given":"Rixu","family":"Cong","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013xs5b60","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Advanced Innovation Center for Human Brain Protection, Capital Medical 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