Introduction of SLC6A8
SLC6A8 (solute carrier family 6 member 8), encoded by the SLC6A8 gene, is also known as sodium- and chloride-dependent creatine transporter 1 (CT1). SLC6A8 gene, containing 13 exons, is mapped to the long arm of the sex chromosome Xq28, and there are multiple transcript variants encoding different isoforms. The transporter SLC6A8 is a multi-pass membrane protein required for the uptake of creatinine in the skeletal and cardiac muscle. SLC6A8 is predominantly expressed in skeletal muscle and kidney, as well as other diverse tissues, including brain, heart, kidney, small intestine, colon, testis, prostate, etc. Regulated by AMP activated kinase, cyclosporine A, mTOR, serum and glucocorticoid inducible kinase isoforms and so on, SLC6A8 expression is largely increased by growth hormone.
|Basic Information of SLC6A8|
|Protein Name||Sodium- and chloride-dependent creatine transporter 1|
|Organism||Homo sapiens (Human)|
Function of SLC6A8 Membrane Protein
As a member of the superfamily of Na+, Cl- coupled transporters for neurotransmitters (e.g. dopamine, GABA, serotonin and norepinephrine), amino acids (e.g. glycine) as well as the organic osmolytes betaine and taurine, SLC6A8 mediates the transportation of creatine into and out of cells. Creatine is synthesized primarily in the liver, kidneys, and pancreas and then transported to other tissues to participate in different physiological processes. It is documented that creatine in brain can be recognized as a neuromodulator and plays an important role in the energy homeostasis of the nervous system. The abundance of SLC6A8 in skeletal muscle is closely associated with muscle physiology, and inhibition of creatine transport in experimental animals causes muscle weakness. In brain, SLC6A8 is predominantly expressed in the cortical and subcortical regions, involved in motor and sensory processing, learning, memory, and regulation of emotion-related behavior. Mutations of SLC6A8 result in X-linked cerebral creatine transporter deficiency (CTD) syndrome, characterized by reduced intra-cerebral creatine, delays in speech and language development, intellectual disabilities, behavioral disturbance, and in some cases, seizures.
Fig.1 Locations of missense and 3 bp deletions in SLC6A8 protein. Missense mutations with a residual activity are marked by an asterisk (*). (van de Kamp,2013)
Application of SLC6A8 Membrane Protein in Literature
In this article, the authors identified a new mutation of SLC6A8 in a child with X-linked cerebral creatine deficiency, characterized by increased urinary creatine/creatinine ratio, abnormal brain proton magnetic resonance spectroscopy and reduced creatine transport, and the mutation is hemizygous in the child and not detected in his mother.
The authors injected cRNA encoding SLC6A8 into Xenopus laevis oocytes with or without wild-type or mutant SPAK/ OSR1, and they revealed that coexpression of wild-type SPAK and of T233ESPAK, wild-type OSR1, T185EOSR1 and T185AOSR1 significantly negatively regulated SLC6A8 activity. So SPAK and OSR1 can be recognized as negative regulators of the creatine transporter SLC6A8.
The authors used two-electrode voltage-clamp technology to test creatine-induced current and they found that coexpression of Klotho protein can significantly increase creatine-induced current in Slc6A8 expressing Xenopus oocytes.
This article used the Xenopus oocyte expression assay to demonstrate that the creatine-induced current is significantly increased by JAK3 inhibitor WHI-P154 (22 µM) in CreaT and JAK3 coexpressing oocytes. So JAK3 is a powerful negative regulator of SLC6A8.
This article performed a retrospective study of creatine transporter gene (SLC6A8) in 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation and presented different phenotype and genotype.
SLC6A8 Preparation Options
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