FIGURE 7.
Proposed model for an additive rescue of the function of α1(A322D) subunits using both EerI and SAHA. VCP extracts misfolded α1(A322D) subunits from the ER membrane to the cytosol for degradation through ERAD. SAHA treatment promotes the folding and trafficking of mutant subunits posttranslationally by enhancing calnexin and BiP-assisted folding. EerI treatment inhibits VCP-mediated ERAD and accumulates more mutant subunits in the ER, which can be further rescued by SAHA treatment. Therefore, coapplication of SAHA and EerI yields an additive restoration of the function of mutant subunits. Red asterisk, A322D mutation in the α1 subunit. The folded subunit schematics are constructed using the crystal structure of GABAA receptor β3 subunits (PDB code 4COF) (48).