Defining the blanks – Pharmacochaperoning of SLC6 transporters and ABC transporters

Chiba, Peter; Freissmuth, Michael; Stockner, Thomas

doi:10.1016/j.phrs.2013.11.009

Cited by 41 publications

(60 citation statements)

References 104 publications

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“…GlyT2 oligomerization was previously shown after transporter crosslinking (49). Our data confirm that oligomer formation is required for ER export, as demonstrated for other SLC6 transporters (26). Therefore, the immature GlyT2 forms appear to bind to CNX prior to the formation of oligomers, and they are subsequently exported from the ER to continue transporter maturation.…”

Section: Discussionsupporting

confidence: 84%

“…TM1a is connected to internal loop 1, which in turn is hydrogen-bonded to the C-terminal latch of the transporter. In several SLC6 members, this region contains the binding site for the cargo receptor of the COPII complex Sec24 that permits ER export (26,39), and C-terminal deletion mutants of GlyT2 are retained in the ER (32). We have demonstrated that the interaction of wild-type GlyT2 with Sec24D is altered in the S512R mutant.…”

Section: Discussionmentioning

confidence: 84%

“…In addition, oligomer assembly is a prerequisite to export the SLC6 transporters from the ER and for their subsequent delivery to the plasma membrane (25). Accordingly, a model has been proposed in which transporter intermediates are engaged by ER chaperones, and they are delivered to the coatomer protein II (COPII) prior to forming oligomers that can subsequently be exported out of the ER (25,26). In the present study, we characterize the features and behavior of the dominant negative hyperekplexia mutant in the early secretory pathway.…”

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confidence: 99%

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Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Arribas-González

Juan-Sanz

Aragón

et al. 2015

Journal of Biological Chemistry

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Background: Hyperekplexia is caused by defective glycinergic neurotransmission. Results: A dominant negative glycine transporter-2 mutant is trapped in a calnexin-bound state and retains wild type GlyT2 in the endoplasmic reticulum. Conclusion: Chemical chaperones rescue the folding defect of the mutant and overcome its dominant negative effect. Significance: This opens the way to revert the dominant negative effect exerted by the mutant associated with hyperekplexia in neurons.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

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Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Arribas-González

Juan-Sanz

Aragón

et al. 2015

Journal of Biological Chemistry

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“…However previous work has not assessed the ability of pharmacological chaperones to rescue disease-relevant mutations. Disease relevant mutations are not restricted to the C terminus but are instead found throughout the protein clustered at the protein-lipid interface (36). We, therefore, tested bupropion and ibogaine on four DTDS mutations: L224P, A314V, R445C, and P529L.…”

Section: Pharmacological Chaperones Of the Dopamine Transportermentioning

confidence: 99%

Pharmacological Chaperones of the Dopamine Transporter Rescue Dopamine Transporter Deficiency Syndrome Mutations in Heterologous Cells

Beerepoot¹,

Lam²,

Salahpour

2016

Journal of Biological Chemistry

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A number of pathological conditions have been linked to mutations in the dopamine transporter gene, including hereditary dopamine transporter deficiency syndrome (DTDS). DTDS is a rare condition that is caused by autosomal recessive loss-offunction mutations in the dopamine transporter (DAT), which often affects transporter trafficking and folding. We examined the possibility of using pharmacological chaperones of DAT to rescue DTDS mutations. After screening a set of known DAT ligands for their ability to increase DAT surface expression, we found that bupropion and ibogaine increased DAT surface expression, whereas others, including cocaine and methylphenidate, had no effect. Bupropion and ibogaine increased wild type DAT protein levels and also promoted maturation of the endoplasmic reticulum (ER)-retained DAT mutant K590A. Rescue of K590A could be blocked by inhibiting ER to Golgi transport using brefeldin A. Furthermore, knockdown of coat protein complex II (COPII) component SEC24D, which is important in the ER export of wild type DAT, also blocked the rescue effects of bupropion and ibogaine. These data suggest that bupropion and ibogaine promote maturation of DAT by acting as pharmacological chaperones in the ER. Importantly, both drugs rescue DAT maturation and functional activity of the DTDS-associated mutations A314V and R445C. Together, these results are the first demonstration of pharmacological chaperoning of DAT and suggest this may be a viable approach to increase DAT levels in DTDS and other conditions associated with reduced DAT function. The dopamine transporter (DAT)4 is responsible for controlling levels of extracellular dopamine and maintaining dopamine stores by transporting dopamine back into neurons after release (1, 2). DAT is part of the Na ϩ /Cl Ϫ -dependent neurotransmitter symporter solute carrier 6 (SLC6) family, which also includes the serotonin, norepinephrine, taurine, and GABA transporters (GAT) (3). A variety of pathological conditions have been associated with mutations in both coding and non-coding regions of the DAT gene (SLC6A3), most of which result in reduced DAT function (4 -7). A recently discovered condition, hereditary DAT deficiency syndrome (DTDS) is caused by autosomal recessive loss-of-function mutations in DAT (6,8,9). The disorder is characterized by parkinsonismdystonia and elevated dopamine metabolites in the cerebrospinal fluid. To date, very few diagnosed DTDS patients have survived to adulthood; the majority of patients die in infancy or adolescence (8, 9). When expressed in heterologous cells, DTDS mutations prevent DAT protein maturation past the endoplasmic reticulum (ER) and result in reduction or elimination of dopamine uptake activity (9). ER retention is a common consequence of mutations in membrane proteins and does not necessarily reflect complete misfolding (10). However, the quality control in the ER is so stringent that mutated proteins that are otherwise partially or completely functional can be retained and degraded (11). Indeed, folding of eve...

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“…Last but not least, the communication between protomers may have repercussions that go beyond the actions of amphetamines. There are several variations in the coding sequence of SLC6 transporters, some of which are associated with folding defects and thus giving rise to overt clinical phenotypes (Chiba et al 2014). However, there are also single-nucleotide polymorphisms, which trigger changes in the coding sequence, which give rise to functional transporters, e.g.…”

Section: The Biological Importance Of Cooperativity Between Transportmentioning

confidence: 99%

Cooperativity between individual transporter protomers: new data fuelling old complexes

Sitte¹,

Schütz

Freissmuth³

2015

Journal of Neurochemistry

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Neurotransmitter transporters are arranged in an oligomeric quaternary structure as evidenced by crosslinking or fluorescence resonance energy transfer (FRET)‐microscopy. In a study by Zhen and colleagues highlighted by this Editorial in the current issue of Journal of Neurochemistry, the combination of mutant and wild‐type dopamine transporter (DAT) has been used to establish the cooperation between transporter protomers; the DAT mutant version has an altered affinity for the radiolabelled inhibitor [3H]CFT. Zhen and colleagues predict how saturation‐binding curves ought to look, if the two binding sites (i.e. of the wild type and the mutant DAT) operated independently. The results are clear‐cut: the experimental observations are inconsistent with curves obtained by mixing independent binding sites. Thus, by definition, the binding sites cooperate. Read the full article ‘Dopamine transporter oligomerization: impact of combining protomers with differential cocaine analog binding affinities’ on page 167.

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Defining the blanks – Pharmacochaperoning of SLC6 transporters and ABC transporters

Abstract: Graphical abstract

Cited by 41 publications

References 104 publications

Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Pharmacological Chaperones of the Dopamine Transporter Rescue Dopamine Transporter Deficiency Syndrome Mutations in Heterologous Cells

Cooperativity between individual transporter protomers: new data fuelling old complexes

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