Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric acid type A receptor membrane trafficking

γ-Aminobutyric acid type A receptors (GABAARs) are the major sites of fast synaptic inhibition in the brain. An essential determinant for the efficacy of synaptic inhibition is the regulation of GABAAR cell surface stability. Here, we have examined the regulation of GABAAR endocytic sorting, a critical regulator of cell surface receptor number. In neurons, rapid constitutive endocytosis of GABAARs was evident. Internalized receptors were then either rapidly recycled back to the cell surface, or on a slower time scale, targeted for lysosomal degradation. This sorting decision was regulated by a direct interaction of GABAARs with Huntingtin-associated protein 1 (HAP1). HAP1 modulated synaptic GABAAR number by inhibiting receptor degradation and facilitating receptor recycling. Together these observations have identified a role for HAP1 in regulating GABAAR sorting, suggesting an important role for this protein in the construction and maintenance of inhibitory synapses