Significance of N-Glycosylation and Sialylation of GABA Transporter 1

Abstract

GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the central nervous system (CNS). GABA reuptake by GABA transporters from the synaptic cleft is one important mechanism in the regulation of GABA activity, whose impairment is involved in the CNS diseases such as Parkinson disease, epilepsy, depression, and Alzheimer disease. The GABA transporter 1 (GAT1) belongs to a family of secondary active systems that are driven by the electrochemical gradients generated by Na⁺ and Cl⁻ ions, respectively. GAT1 is a glycoprotein possessing three N-glycosylation sites. In this paper, we review our recent results of the biological role of N-glycosylation, peripheral trimming of the N-glycans, and sialylation of GAT1. The cotranslational N-glycosylation, but not the peripheral trimming of N-glycans, is involved in the regulation of the stability and trafficking of GAT1. The GABA uptake activity of GAT1 was found to be regulated by N-glycans. Specifically, the terminal sialic acid residues, the peripheral structures of N-glycans play a crucial regulatory role in the GABA transport process. The negative charge of sialic acids influences the binding of GAT1 to sodium ion, while the structure of sialic acids participates directly in the GABA translocation process of GAT1.

Keywords:

• γ-Aminobutyric acid (GABA)
• GABA transporter 1
• N-glycosylation
• N-glycans
• sialic acid

ACKNOWLEDGEMENTS

We are grateful to Dr. Luis Da Silva Azevedo for scientific discussions of this manuscript. This work was supported by Deutsche Forschungsgemeinschaft Bonn (SFB 449) and the Sonnenfeld-Stiftung Berlin.