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Mechanisms underlying the epileptic phenotype associated with the alpha-1 A322D mutation in the GABA-A receptor Bradley, Clarrisa Ann


Epilepsy is a common neurological disorder with a strong hereditary component. A mutation in the α1 subunit (A322D) of the GABA-A receptor is responsible for juvenile myoclonic epilepsy in a large Canadian family. Previous work has identified that this mutation affects the function of GABA-A receptors, expressed in HEK293 cells. Here I have examined the underlying mechanisms of this dysfunction and shown that the mutation reduces the cell surface expression of the GABA-A receptor, promotes association with the endoplasmic reticulum chaperone calnexin, enhances degradation and accelerates the degradation rate of the subunits approximately 2.5 fold. I have also found that the mutation causes the receptor to be degraded by a lysosomal-dependent process. Furthermore, I find that the mutation results in receptors that are inserted into the plasma membrane but are more rapidly endocytosed by a dynamin and caveolin-dependent mechanism. These results suggest that the mutant subunit can form trafficking-competent receptors that have a shorter lifetime on the plasma membrane. Collectively, my results strongly implicate defects in both the biogenesis and trafficking of the GABA-A receptors, as part of the mechanistic basis for the epileptic phenotype observed.

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