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Bile acids gate dopamine transporter mediated currents

Tiziana Romanazzi, Daniele Zanella, Mary Hongying Cheng, Behrgen Smith, View ORCID ProfileAngela M. Carter, View ORCID ProfileAurelio Galli, View ORCID ProfileIvet Bahar, View ORCID ProfileElena Bossi
doi: https://doi.org/10.1101/2021.09.13.459497
Tiziana Romanazzi
1Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
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Daniele Zanella
2Department of Surgery, University of Alabama at Birmingham, Alabama 35233, USA
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Mary Hongying Cheng
3Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Behrgen Smith
4Department of Physics and Chemistry, Biomolecular Engineering, Milwaukee School of Engineering, Milwaukee, WI 54301, USA
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Angela M. Carter
2Department of Surgery, University of Alabama at Birmingham, Alabama 35233, USA
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Aurelio Galli
2Department of Surgery, University of Alabama at Birmingham, Alabama 35233, USA
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Ivet Bahar
3Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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  • For correspondence: elena.bossi@uninsubria.it bahar@pitt.edu
Elena Bossi
1Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
5Center for Research in Neuroscience, University of Insubria, Varese, Italy
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  • For correspondence: elena.bossi@uninsubria.it bahar@pitt.edu
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Abstract

Bile acids (BAs) are molecules derived from cholesterol that are involved in dietary fat absorption. New evidence supports an additional role for BAs as regulators of brain function. Interestingly, sterols such as cholesterol interact with monoamine transporters (MAT), including the dopamine (DA) transporter (DAT) which plays a key role in DA neurotransmission and reward circuitries in the brain. The present study explores interactions of the BA, obeticholic acid (OCA), with DAT and mechanistically defines the regulation of DAT activity via both electrophysiology and molecular modeling. We express murine DAT (mDAT) in Xenopus laevis oocytes and confirm that DA induces an inward current that reaches a steady-state at a negative membrane voltage. Next, we show that OCA triggers an inward current through DAT that is Na+ dependent and not regulated by intracellular calcium. OCA also inhibits the DAT-mediated Li+ leak current, a feature that parallels DA action and indicates direct binding to the transporter. Interestingly, OCA does not alter DA affinity nor the ability of DA to promote a DAT-mediated inward current, suggesting that the interaction of OCA with the transporter is non-competitive, in regard to DA. The current induced by OCA is transient in nature, returning to baseline in the continued presence of the BA. To understand the molecular mechanism of how OCA affects DAT electrical activity, we performed docking simulations. These simulations revealed two potential binding sites that provide important insights into the potential functional relevance of the OCA-DAT interaction. First, in the absence of DA, OCA binds DAT through interactions with D421, a residue normally involved in coordinating the binding of the Na+ ion to the Na2 binding site (Borre et al., 2014;Cheng and Bahar, 2015). Furthermore, we uncover a separate binding site for OCA on DAT, of equal potential functional impact, that is facilitated through the residues DAT R445 and D436. This binding may stabilize the inward-facing open (IFo) state by preventing the re-formation of the IF gating salt bridges, R60-D436 and R445-E428, that are required for DA transport. This study suggests that BAs may represent novel pharmacological tools to regulate DAT function, and possibly, associated behaviors.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 14, 2021.
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Bile acids gate dopamine transporter mediated currents
Tiziana Romanazzi, Daniele Zanella, Mary Hongying Cheng, Behrgen Smith, Angela M. Carter, Aurelio Galli, Ivet Bahar, Elena Bossi
bioRxiv 2021.09.13.459497; doi: https://doi.org/10.1101/2021.09.13.459497
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Bile acids gate dopamine transporter mediated currents
Tiziana Romanazzi, Daniele Zanella, Mary Hongying Cheng, Behrgen Smith, Angela M. Carter, Aurelio Galli, Ivet Bahar, Elena Bossi
bioRxiv 2021.09.13.459497; doi: https://doi.org/10.1101/2021.09.13.459497

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