Mechanisms involved in the reduction of GABAA receptor α1-subunit expression caused by the epilepsy mutation A322D in the trafficking-competent receptor

A mutation in the alpha 1-subunit (A322D) of GABA(A)Rs is responsible for juvenile myoclonic epilepsy in a large Canadian family. Previous work has identified that this mutant affects the cell expression and function of recombinant GABAARs, expressed in HEK293 cells. Here we have extended these observations by showing that the mutation promotes association with the endoplasmic reticulum chaperone calnexin and accelerates the degradation rate of the subunits similar to 2.5-fold. We also find that the mutation causes the subunit to be degraded largely by a lysosomal-dependent process. Furthermore, we find that the mutation results in receptors that are inserted into the plasma membrane but are more rapidly endocytosed by a dynamin and caveolin1-dependent mechanism. These results suggest that the mutant subunit can form functional receptors, but that these have a shorter lifetime on the plasma membrane.