SLC6 Transporter Folding Diseases and Pharmacochaperoning

摘要: The human genome encodes 19 genes of the solute carrier 6 (SLC6) family; non-synonymous changes in coding sequence give rise to mutated transporters, which are misfolded and thus cause diseases affected individuals. Prominent examples include mutations transporters for dopamine (DAT, SLC6A3), creatine (CT1, SLC6A8), glycine (GlyT2, SLC6A5), result infantile dystonia, mental retardation, hyperekplexia, respectively. Thus, there is an obvious unmet medical need identify compounds, can remedy folding deficit. pharmacological correction defects was originally explored mutants serotonin transporter (SERT, SLC6A4), were created study COPII-dependent export from endoplasmic reticulum. This led serendipitous discovery pharmacochaperoning action ibogaine. Ibogaine its metabolite noribogaine also rescue several disease-relevant DAT. Because pharmacology DAT SERT exceptionally rich, it not surprising that additional compounds have been identified, folding-deficient mutants. These only interest restoring function children. They likely serve as useful tools interrogate trajectory transporter. initiate a virtuous cycle: if principles underlying SLC6 understood, design pharmacochaperones ought be facilitated.