A neuronal role of the Alanine-Serine-Cysteine-1 transporter (SLC7A10, Asc-1) for glycine inhibitory transmission and respiratory pattern

Guillaume Mesuret,Hazem Safory,Swen Hülsmann,Sepideh Khabbazzadeh,Herman Wolosker,Anne M Bischoff

doi:10.1038/s41598-018-26868-6

Abstract

The Alanine-Serine-Cysteine-1 transporter (SLC7A10, Asc-1) has been shown to play a role in synaptic availability of glycine although the exact mechanism remains unclear. We used electrophysiological recordings and biochemical experiments to investigate the role of Asc-1 transporter in glycinergic transmission in the brainstem respiratory network. Using both the Asc-1 substrate and transportable inhibitor D-isoleucine (D-Ile), and the non-transportable Asc-1 blocker Lu AE00527 (Lu), we found that D-Ile reduces glycinergic transmission and increases glycine release via hetero-exchange, whereas Lu has no acute effect on glycinergic synaptic transmission. Furthermore, D-Ile increases the frequency and reduces amplitude of the phrenic nerve activity in the arterially-perfused working heart brainstem preparation. These results suggest a role of Asc-1 in modulating presynaptic glycine levels that can impact on the respiratory network.

Highlights

Transport of glycine in the brain is carried out mainly by the glial glycine transporter 1 (SLC6A9 or GlyT1), the neuronal glycine transporter 2 (SLC6A5 or GlyT2), which accumulates glycine in the cytosol of the presynapse, and the vesicular amino acid transporter (SLC32A1 or VIAAT)[6,7,8,9]
For the following analysis of the role of Asc-1 on glycinergic transmission, we decided to use only glycinergic IPSCs that were recorded from non-glycinergic neurons
We showed that the transportable Asc-1 inhibitor D-Ile reduces the glycinergic post synaptic currents of putative excitatory neurons, while Lu AE00527 did not

Summary

Introduction

Transport of glycine in the brain is carried out mainly by the glial glycine transporter 1 (SLC6A9 or GlyT1), the neuronal glycine transporter 2 (SLC6A5 or GlyT2), which accumulates glycine in the cytosol of the presynapse, and the vesicular amino acid transporter (SLC32A1 or VIAAT)[6,7,8,9]. The latter transports both -aminobutyric acid (GABA) and glycine into synaptic vesicles[10,11,12,13]. To assess the functional role of Asc-1 in the respiratory network, we analyzed the phrenic nerve activity using the working heart brain preparation (WHBP)

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