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SLC6 Transporter Folding Diseases and Pharmacochaperoning.

Michael Freissmuth, Thomas Stockner, Sonja Sucic

Handbook of experimental pharmacology 2018 DOI: 10.1007/164_2017_71 (opens in new tab)

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AI-extracted from the abstract
Characteristics Review Peer reviewed
Interventions Ibogaine Noribogaine
Topics Ibogaine
Keywords Er export Folding diseases Heat-shock proteins Pharmacochaperones Slc6 transporters Chemical chaperones Drug discovery Therapeutic agents Membrane proteins Solute carriers Protein function Protein rescue Misfolded proteins Folding defects Conformational diseases Infantile dystonia Protein misfolding Protein folding Protein quality control Protein trafficking Protein maturation Protein structure Protein biogenesis Endoplasmic reticulum Cellular transport
Citations 44
Key findings Pharmacochaperones such as ibogaine can rescue misfolded SLC6 transporter mutants, offering therapeutic potential for diseases caused by folding defects.

Abstract

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

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