Introduction of SLC6A9
SLC6A9 (solute carrier family 6 member 9) is also known as sodium- and chloride-dependent glycine transporter 1 (GlyT-1), one of the two subtypes of glycine transporters (GlyTs). The SLC6A9 gene is mapped to the short (p) arm of chromosome 1 at position 34.1 (1p34.1), which contains 14 exons encoding a multi-pass membrane protein. There are many transcript variants encoding different isoforms in this gene. The architecture of SLC6A9 is characterized by 12 transmembrane segments (12TM), an N-terminus and a C-terminus, which regulates transporter trafficking in plasma membrane and cellular surface density. This protein contains PDZ binding motif responsible for SLC6A9 interaction with trafficking and clustering proteins. SLC6A9 is widely expressed in the central nervous system (CNS) and peripheral tissues, such as liver, kidney, lung, pancreas, etc.
|Basic Information of SLC6A9|
|Protein Name||Sodium- and chloride-dependent glycine transporter 1|
|Organism||Homo sapiens (Human)|
Function of SLC6A9 Membrane Protein
As important plasmalemmal neurotransmitter transporters, GlyT-1 can stop the signaling of glycine by mediating its reuptake from the synaptic cleft back into the presynaptic neurons. In brain, the abundance of SLC6A9 on the plasma membrane of glutamatergic neurons and synaptic vesicles indicates its role in regulation of glycine levels in N-methyl-D-aspartate (NMDA) glutamate receptor-mediated neurotransmission. Moreover, it is documented that SLC6A9 can combine with SLC6A5 (GlyT2) in astrocytes within caudal brain areas and their stabilization/expression is regulated by GSK3β. The interaction is responsible for the termination of glycine-mediated synaptic activity through removal of neurotransmitter from synaptic cleft. Beyond the function in brain, SLC6A9 has the potency to mediate the glycine transport at the inner blood-retinal barrier and in cortical fiber cells, suggesting an important role in regulating the glycine concentration in the neural retina. SLC6A9 is also associated with autosomal recessive glycine encephalopathy with normal serum glycine, schizophrenia and cognitive disorders and human essential hypertension. In clinical studies, SLC6A9 inhibitors have constituted a new class of antictogenic drugs to elevate the extracellular synaptic glycine concentration.
Fig.1 Topology plot of the structure adopted by SLC6A9. (Bröer, 2011)
Application of SLC6A9 Membrane Protein in Literature
The authors evaluated three single nucleotide polymorphisms (SNPs) (rs2286245, rs3791124, and rs2486001) of SLC6A9 and explored their roles in essential hypertension (EH). Data revealed an association of SLC6A9 gene polymorphisms with essential hypertension in Japanese population.
This article demonstrated that brain-derived neurotrophic factor (BDNF) can decrease GlyT1- and GlyT2- mediated [(3) H]glycine transport in astrocytes and a Rho family-specific blocker (toxin B) can inhibit BDNF action. While toxin B has been associated with TrkB-T1, so BDNF can act as TrkB-T1 receptors to regulate GlyT1 and GlyT2 in astrocytes through Rho-GTPase activity.
The authors studied a consanguineous family with one non-ketotic hyperglycinemia (NKH) child and revealed a novel homozygous missense variant in exon 9 of SLC6A9, firstly verified that mutation of the glycine transporter (SLC6A9 p.Ser407Gly) can be associated with NKH in humans.
The review summarized the multiple functions of various amino acid transporters and their mutations in disorders. These transporters may affect neuronal excitability, whole-body homoeostasis, malabsorption and renal problems, tumour progression, etc.
This article demonstrated that GLYT1 can combine GLYT2 to form chimeric transporters and this complex was inhibited by the sarcosine derivative N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS). The inhibition occurred in TM1 or TM3 of GLYT1 on GLYT2 structure, especially the N-terminal portion of GLYT1 including residue E40.
SLC6A9 Preparation Options
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