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JOURNAL ARTICLE
RESEARCH SUPPORT, N.I.H., INTRAMURAL
RESEARCH SUPPORT, NON-U.S. GOV'T
The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats.
Journal of Biological Chemistry 2017 July 8
The dopamine transporter (DAT) regulates dopamine (DA) neurotransmission by recapturing DA into the presynaptic terminals and is a principal target of the psychostimulant cocaine. The sigma-1 receptor (σ1 R) is a molecular chaperone, and its ligands have been shown to modulate DA neuronal signaling, although their effects on DAT activity are unclear. Here, we report that the prototypical σ1 R agonist (+)-pentazocine potentiated the dose response of cocaine self-administration in rats, consistent with the effects of the σR agonists PRE-084 and DTG (1,3-di- o -tolylguanidine) reported previously. These behavioral effects appeared to be correlated with functional changes of DAT. Preincubation with (+)-pentazocine or PRE-084 increased the Bmax values of [3 H]WIN35428 binding to DAT in rat striatal synaptosomes and transfected cells. A specific interaction between σ1 R and DAT was detected by co-immunoprecipitation and bioluminescence resonance energy transfer assays. Mutational analyses indicated that the transmembrane domain of σ1 R likely mediated this interaction. Furthermore, cysteine accessibility assays showed that σ1 R agonist preincubation potentiated cocaine-induced changes in DAT conformation, which were blocked by the specific σ1 R antagonist CM304. Moreover, σ1 R ligands had distinct effects on σ1 R multimerization. CM304 increased the proportion of multimeric σ1 Rs, whereas (+)-pentazocine increased monomeric σ1 Rs. Together these results support the hypothesis that σ1 R agonists promote dissociation of σ1 R multimers into monomers, which then interact with DAT to stabilize an outward-facing DAT conformation and enhance cocaine binding. We propose that this novel molecular mechanism underlies the behavioral potentiation of cocaine self-administration by σ1 R agonists in animal models.
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