SLC6A5 Membrane Protein Introduction

Introduction of SLC6A5

SLC6A5, also known as GlyT2, is encoded by SLC6A5 gene. It belongs to the solute carrier family 6 which has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. It is a sodium- and chloride-dependent glycine neurotransmitter transporter which controls the concentration of neurotransmitters at central synapses. GlyT2 is found in glycinergic axons, exhibits a 3 Na⁺/1 Cl⁻/1 glycine stoichiometry and plays an essential role in maintaining a high presynaptic pool of neurotransmitter at glycinergic synapses. Meanwhile, many studies conducted on SLC6A5 show that its variants are related to hyperekplexia.

Basic Information of SLC6A5
Protein Name	Sodium- and chloride-dependent glycine transporter 2
Gene Name	SLC6A5
Aliases	GLYT2, NET1
Organism	Homo sapiens (Human)
UniProt ID	Q9Y345
Transmembrane Times	12
Length (aa)	797
Sequence	MDCSAPKEMNKLPANSPEAAAAQGHPDGPCAPRTSPEQELPAAAAPPPPRVPRSASTGAQTFQSADARACEAERPGVGSCKLSSPRAQAASAALRDLREAQGAQASPPPGSSGPGNALHCKIPFLRGPEGDANVSVGKGTLERNNTPVVGWVNMSQSTVVLATDGITSVLPGSVATVATQEDEQGDENKARGNWSSKLDFILSMVGYAVGLGNVWRFPYLAFQNGGGAFLIPYLMMLALAGLPIFFLEVSLGQFASQGPVSVWKAIPALQGCGIAMLIISVLIAIYYNVIICYTLFYLFASFVSVLPWGSCNNPWNTPECKDKTKLLLDSCVISDHPKIQIKNSTFCMTAYPNVTMVNFTSQANKTFVSGSEEYFKYFVLKISAGIEYPGEIRWPLALCLFLAWVIVYASLAKGIKTSGKVVYFTATFPYVVLVILLIRGVTLPGAGAGIWYFITPKWEKLTDATVWKDAATQIFFSLSAAWGGLITLSSYNKFHNNCYRDTLIVTCTNSATSIFAGFVIFSVIGFMANERKVNIENVADQGPGIAFVVYPEALTRLPLSPFWAIIFFLMLLTLGLDTMFATIETIVTSISDEFPKYLRTHKPVFTLGCCICFFIMGFPMITQGGIYMFQLVDTYAASYALVIIAIFELVGISYVYGLQRFCEDIEMMIGFQPNIFWKVCWAFVTPTILTFILCFSFYQWEPMTYGSYRYPNWSMVLGWLMLACSVIWIPIMFVIKMHLAPGRFIERLKLVCSPQPDWGPFLAQHRGERYKNMIDPLGTSSLGLKLPVKDLELGTQC

Function of SLC6A5 Membrane Protein

SLC6A5 is mainly expressed in the testis and brain. It is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft and its activity modulates intra and extracellular glycine concentrations. Recent studies indicate that SLC6A5 variants are strongly associated with human startle disease. In addition, researches have confirmed that SCL6A5 mediates synaptic glycine recycling which constitutes the main source of releasable transmitter at glycinergic synapses.

SLC6A5 Membrane Protein Introduction Fig.1 Structure and amino acid sequence of human GlyT2 (SLC6A5) gene. (Rees, 2006)

Application of SLC6A5 Membrane Protein in Literature

López-Corcuera B., et al. Hyperekplexia-associated mutations in the neuronal glycine transporter 2. Neurochem Int. 2019, 123:95-100. PubMed ID: 29859229

This article reports the association between the SLC6A5 variants and hyperekplexia or startle disease. These results indicate that several SLC6A5 mutations have potential therapeutic effects in hyperekplexia.
Hülsmann S., et al. GlyT2-dependent preservation of MECP2-expression in inhibitory neurons improves early respiratory symptoms but does not rescue survival in a mouse model of Rett syndrome. Front Physiol. 2016, 7:385. PubMed ID: 27672368

This article analyzes the expression level of the Cre-recombinase (Cre) in inhibitory neurons under the control of the GlyT2 promotor. The data suggest that alterations in inhibitory neurons are important for the development of the respiratory phenotype in Rett syndrome.
Villarejo-López L., et al. P2X receptors up-regulate the cell-surface expression of the neuronal glycine transporter GlyT2. Neuropharmacology. 2017, 125:99-116. PubMed ID: 28734869

Authors in this group analyze the expression level of SLC6A5 in response to P2X receptor agonists. The data show that the impact of P2X3 receptor activation on glycinergic neurotransmission involves the modulation of GlyT2 expression or activity.
Arribas-González E., et al. Molecular basis of the dominant negative effect of a glycine transporter 2 mutation associated with hyperekplexia. J Biol Chem. 2015, 290(4):2150-65. PubMed ID: 25480793

This article examines the association between the SLC6A5 variants and hyperekplexia in the endoplasmic reticulum (ER). The results suggest that wild-type GlyT2 is highly expressed, and the S512R mutant forms oligomers with wild-type GlyT2 causing its retention in the ER.
Milanese M.H.B, et al. A new function for glycine GlyT2 transporters: Stimulation of γ-aminobutyric acid release from cerebellar nerve terminals through GAT1 transporter reversal and Ca(2+)-dependent anion channels. J Neurosci Res. 2014, 92(3):398-408. PubMed ID: 24273061

This article reveals a novel function of GlyT2 transporters by confocal microscopy analysis. The data demonstrate that GlyT2 transporters not only take up glycine to replenish synaptic vesicles but also mediate the release of GABA by reversal of GAT1 and permeation through anion channels.

SLC6A5 Preparation Options

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Reference

Rees M I, et al. (2006). Mutations in the human GlyT2 gene define a presynaptic component of human startle disease. Nat Genet. 38(7), 801-6.

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