Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Abstract

In addition to being involved in protein biosynthesis and metabolism, the amino acid glycine is the most important inhibitory neurotransmitter in caudal regions of the brain. These functions require a tight regulation of glycine concentration not only in the synaptic cleft, but also in various intracellular and extracellular compartments. This is achieved not only by confining the synthesis and degradation of glycine predominantly to the mitochondria, but also by the action of high-affinity large-capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminals or glial cells surrounding the synapses. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their synergistic functional interaction is only poorly understood. In this review, we summarize our current knowledge of the two high-affinity transporters for glycine, the sodium-dependent glycine transporters 1 (GlyT1; SLC6A9) and 2 (GlyT2; SLC6A5) and the alanine–serine–cysteine-1 transporter (Asc-1; SLC7A10).

Chronic intermittent hypoxia enhances glycinergic inhibition in nucleus tractus solitarius

“…Glycine and serine are released both from neurons and astrocytes ( 58 – 60 ). In addition to its inhibitory effects, glycine is an important modulator of NMDA receptors ( 61 ). d -serine also functions as an agonist for the glycine binding sight on the NMDA receptor ( 61 , 62 ).…”

“…In addition to its inhibitory effects, glycine is an important modulator of NMDA receptors ( 61 ). d -serine also functions as an agonist for the glycine binding sight on the NMDA receptor ( 61 , 62 ). Release of d -serine and its binding to NMDA receptors contributes to activation of the respiratory network and could participate in central chemoreception ( 58 ).…”

“…Release of d -serine and its binding to NMDA receptors contributes to activation of the respiratory network and could participate in central chemoreception ( 58 ). Astrocytes express glycine transporters and regulate the extracellular concentration of both glycine and serine ( 61 ). Our data suggest that some astrocytes in the NTS may express GlyRs and that CIH changes the morphology of some NTS astrocytes.…”

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“…Glycine is synthesized by serine hydroxymethyltransferase within mitochondria, and like GABA, is bound in presynaptic vesicles by VGAT [ 36 , 61 , 62 , 63 ]. Subsequent to release, glycine reuptake from the synaptic cleft occurs at astrocytes and presynaptic terminals, with glycine transporter 1 (GlyT1) predominating in the former, with GlyT2 predominating at presynaptic release sites [ 103 , 104 ] and being the only reliable marker of glycinergic neurons [ 105 ] ( Figure 2 ). In addition, the alanine–serine–cysteine-1 transporter (ASC1) also plays a role in astrocytic and neuronal reuptake [ 106 , 107 ], potentially distinct from those of GlyT1 and GlyT2 [ 105 ].…”

“…Subsequent to release, glycine reuptake from the synaptic cleft occurs at astrocytes and presynaptic terminals, with glycine transporter 1 (GlyT1) predominating in the former, with GlyT2 predominating at presynaptic release sites [ 103 , 104 ] and being the only reliable marker of glycinergic neurons [ 105 ] ( Figure 2 ). In addition, the alanine–serine–cysteine-1 transporter (ASC1) also plays a role in astrocytic and neuronal reuptake [ 106 , 107 ], potentially distinct from those of GlyT1 and GlyT2 [ 105 ]. Corelease and or mixed release of GABA and glycine and inhibitory synapses is not uncommon within the brainstem and spinal cord [ 96 , 108 , 109 ].…”