348 It has been shown that internalization of DAT occurs through a clathrin-dependent pathway and proteins are trafficked to the lysosome for degradation. 347 Furthermore, three ubiquitin conjugation sites (Lys19, Lys27, and Lys35) in the N-terminus of DAT were identified to be essential for PKC-dependent endocytosis of the transporter. 346 It was shown that the PKC activator, PMA, increased DAT ubiquitination, and pretreatment of cells with a PKC inhibitor, bisindolylmaleimide, prevented the increase in ubiquitination induced by PMA. 345 It has been found that PKC is involved in the ubiquitination and endocytosis of DAT. 344 DAT has 12 transmembrane domains with intracellular N- and C-terminal domains. The Na +/K + ATPase provides the concentration gradient and subsequently the driving force for DAT mediated reuptake of dopamine. 343 DAT functions as a cotransporter by binding with two sodium ions and one chloride ion to uptake dopamine into the cell. Functional alterations of DAT in these parts of the brain are associated with a plethora of neurological disorders such as depression, ADHD, Parkinson's disease, and bipolar disorder. 342 The distribution of DAT is widespread in the brain especially in regions pertaining to reward such as the mesolimbic system and regions pertaining to movement such as the substantia nigra. The DAT, encoded by the SLC6A3 gene, is a transmembrane protein responsible for the reuptake of dopamine from the synapse back into the cytosol of dopaminergic neurons. Zhang, in Progress in Molecular Biology and Translational Science, 2016 6.2.1 Dopamine Transporter No effective treatment has been identified l-dopa/carbidopa did not result in improvements in clinical or biochemical parameters. Diagnosis was established by demonstrating the loss-of-function mutation in the SLC6A3 gene. The urinary level of HVA and serum concentration of prolactin were increased. Brain MRI usually shows no abnormalities.ĬSF examination revealed elevation of HVA and normal level of 5-HIAAs. Irritability and feeding difficulties started shortly after birth and progressed to hypotonia, lack of head control, parkinsonism, dystonia, and global developmental delay by early infancy. These children presented with symptoms of infantile parkinsonism-dystonia syndrome. Pathogenic variants of this gene has been reported in 13 children. Dopamine transporter protein (DAT) is encoded by SLC6A3 gene on chromosome 5p15.33.
This transporter protein is involved in reuptake of dopamine by the presynaptic neurons, and its deficiency causes depletion of dopamine and thus a dopamine deficiency state. Kliegman MD, in Nelson Textbook of Pediatrics, 2020 Dopamine Transporter Protein Deficiency
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