Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric acid type A receptor membrane trafficking.
Gamma-aminobutyric acid type A receptors (GABA(A)Rs) are the major sites of fast synaptic inhibition in the brain. An essential determinant for the efficacy of synaptic inhibition is the regulation of GABA(A)R cell surface stability. Here, we have examined the regulation of GABA(A)R endocytic sorting, a critical regulator of cell surface receptor number. In neurons, rapid constitutive endocytosis of GABA(A)Rs 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 GABA(A)Rs with Huntingtin-associated protein 1 (HAP1). HAP1 modulated synaptic GABA(A)R number by inhibiting receptor degradation and facilitating receptor recycling. Together these observations have identified a role for HAP1 in regulating GABA(A)R sorting, suggesting an important role for this protein in the construction and maintenance of inhibitory synapses.
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Josef T
JT
Kittler
Philip
P
Thomas
Verena
V
Tretter
Yuri D
YD
Bogdanov
Volker
V
Haucke
Trevor G
TG
Smart
Stephen J
SJ
Moss
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004705:Endocytosis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D020798:Two-Hybrid System Techniques
D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D011963:Receptors, GABA-A