Glycine transporter subfamily C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
Two gene products, GlyT1 and GlyT2, are known that give rise to transporters that are predominantly located on glia and neurones, respectively. Five variants of GlyT1 (a,b,c,d & e) differing in their N- and C-termini are generated by alternative promoter usage and splicing, and three splice variants of GlyT2 (a,b & c) have also been identified (see [5,12,14,37] for reviews). GlyT1 transporter isoforms expressed in glia surrounding glutamatergic synapses regulate synaptic glycine concentrations influencing NMDA receptor-mediated neurotransmission [4,13], but also are important, in early neonatal life, for regulating glycine concentrations at inhibitory glycinergic synapses [15]. Homozygous mice engineered to totally lack GlyT1 exhibit severe respiratory and motor deficiencies due to hyperactive glycinergic signalling and die within the first postnatal day [15,38]. Disruption of GlyT1 restricted to forebrain neurones is associated with enhancement of EPSCs mediated by NMDA receptors and behaviours that are suggestive of a promnesic action [43]. GlyT2 transporters localised on the axons and boutons of glycinergic neurones appear crucial for efficient transmitter loading of synaptic vesicles but may not be essential for the termination of inhibitory neurotransmission [16,35]. Mice in which GlyT2 has been deleted develop a fatal hyperekplexia phenotype during the second postnatal week [16] and mutations in the human gene encoding GlyT2 (SLC6A5) have been identified in patients with hyperekplexia (reviewed by [17]). ATB0+ (SLC6A14) is a transporter for numerous dipolar and cationic amino acids and thus has a much broader substrate specificity than the glycine transporters alongside which it is grouped on the basis of structural similarity [10]. ATB0+ is expressed in various peripheral tissues [10]. By contrast PROT (SLC6A7), which is expressed only in brain in association with a subset of excitatory nerve terminals, shows specificity for the transport of L-proline.
Transporters
938
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GlyT1 / SLC6A9
C
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GlyT2 / SLC6A5 C Show summary » |
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ATB0,+ / SLC6A14 C Show summary » |
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PROT / SLC6A7 C Show summary »
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Comments
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Transporters. Br J Pharmacol. 180 Suppl 2:S374-469.
Sarcosine is a selective transportable inhibitor of GlyT1 and also a weak agonist at the glycine binding site of the NMDA receptor [46], but has no effect on GlyT2. This difference has been attributed to a single glycine residue in TM6 (serine residue in GlyT2) [41]. Inhibition of GLYT1 by the sarcosine derivatives NFPS, NPTS and Org 24598 is non-competitive [25-26]. IC50 values for Org 24598 reported in the literature vary, most likely due to differences in assay conditions [7,25]. The tricyclic antidepressant amoxapine weakly inhibits GlyT2 (IC50 92 µM) with approximately 10-fold selectivity over GlyT1 [28]. The endogenous lipids arachidonic acid and anandamide exert opposing effects upon GlyT1a, inhibiting (IC50 ~ 2 µM) and potentiating (EC50 ~ 13 µM) transport currents, respectively [31]. N-arachidonyl-glycine, N-arachidonyl-γ-aminobutyric acid and N-arachidonyl-D-alanine have been described as endogenous non-competitive inhibitors of GlyT2a, but not GlyT1b [11,20,42]. Protons [3] and Zn2+ [21] act as non-competitive inhibitors of GlyT1b, with IC50 values of ~100 nM and ~10 µM respectively, but neither ion affects GlyT2 (reviewed by [40]). Glycine transport by GLYT1 is inhibited by Li+, whereas GLYT2 transport is stimulated (both in the presence of Na+) [34].