GABAA Receptor Trafficking Is Regulated by Protein Kinase Cε and the N-Ethylmaleimide-Sensitive Factor

Disturbances in GABA(A) receptor trafficking contribute to several neurological and psychiatric disorders by altering inhibitory neuro-transmission. Identifying mechanisms that regulate GABA(A) receptor trafficking could lead to better understanding of disease pathogenesis and treatment. Here, we show that protein kinase C epsilon (PKC epsilon) regulates the N-ethylmaleimide-sensitive factor (NSF), an ATPase critical for membrane fusion events, and thereby promotes the trafficking of GABA(A) receptors. Activation of PKC epsilon decreased cell surface expression of GABA(A) receptors and attenuated GABA(A) currents. Activated PKC epsilon associated with NSF, phosphorylated NSF at serine 460 and threonine 461, and increased NSF ATPase activity, which was required for GABA(A) receptor downregulation. These findings identify new roles for NSF and PKC epsilon in regulating synaptic inhibition through downregulation of GABA(A) receptors. Reducing NSF activity by inhibiting PKC epsilon could help restore synaptic inhibition in disease states in which it is impaired.