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bioRxiv · 10.1101/755819

Membrane composition influences the conformation and function of the dopamine transporter in vivo

Fong, W. M.·Erreger, K.·Choi, S. J.·Reddy, I.·Johnson, C. W.·Mosharov, E. V.·Javitch, J. A.·Galli, A.·Yamamoto, A.
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Abstract

The biophysical and biochemical properties of membrane lipids can alter the conformation and function of membrane-spanning proteins, yet the specific, physiological consequence in vivo of changing the membrane milieu for a specific protein has been rarely investigated. Using various genetic approaches to eliminate expression of the membrane-associated protein Flotillin-1, we have found that the lipid environment of the dopamine transporter (DAT) is necessary for mice to respond to amphetamine but not cocaine, because the localization of DAT to cholesterol-rich membranes is required for a DAT conformation that is essential for reverse transport of dopamine. Furthermore, a conditional rather than constitutive loss-of-function approach was necessary to reveal this phenotype, indicating a broader role for membrane-protein interactions that are modulated by Flotillin-1. Taken together, these findings demonstrate how interaction of a transmembrane protein with its membrane environment can regulate distinct events in the vertebrate brain that give rise to specific behavioral outcomes.

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Fong, W. M., Erreger, K., Choi, S. J., Reddy, I., Johnson, C. W., Mosharov, E. V., Javitch, J. A., Galli, A., Yamamoto, A.. 2019-09-05. Membrane composition influences the conformation and function of the dopamine transporter in vivo. https://doi.org/10.1101/755819

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