Single Quantum Dot Imaging Reveals PKCβ-Dependent Alterations in Membrane Diffusion and Clustering of an Attention-Deficit Hyperactivity Disorder/Autism/Bipolar Disorder-Associated Dopamine Transporter Variant

ACS Chemical Neuroscience
Lucas B ThalSandra J Rosenthal

Abstract

The dopamine transporter (DAT) is a transmembrane protein that terminates dopamine signaling in the brain by driving rapid dopamine reuptake into presynaptic nerve terminals. Several lines of evidence indicate that DAT dysfunction is linked to neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BPD), and autism spectrum disorder (ASD). Indeed, individuals with these disorders have been found to express the rare, functional DAT coding variant Val559, which confers anomalous dopamine efflux (ADE) in vitro and in vivo. To elucidate the impact of the DAT Val559 variant on membrane diffusion dynamics, we implemented our antagonist-conjugated quantum dot (QD) labeling approach to monitor the lateral mobility of single particle-labeled transporters in transfected HEK-293 and SK-N-MC cells. Our results demonstrate significantly higher diffusion coefficients of DAT Val559 compared to those of DAT Ala559, effects likely determined by elevated N-terminal transporter phosphorylation. We also provide pharmacological evidence that PKCβ-mediated signaling supports enhanced DAT Val559 membrane diffusion rates. Additionally, our results are complimented with diffusion rates of phosphomimicked an...Continue Reading

Citations

Aug 24, 2019·Journal of Molecular Neuroscience : MN·Feng-Ling XuBao-Jie Wang
Mar 7, 2020·The Journal of Biological Chemistry·Rita R FaganHaley E Melikian
Dec 4, 2019·Biomaterials Science·Lucas B ThalSandra J Rosenthal
May 28, 2019·Frontiers in Medicine·Sylvie ChalonMaria-Joao Ribeiro
Jan 30, 2021·The Journal of Biological Chemistry·Rita R FaganHaley E Melikian
Jun 23, 2021·Nordic Journal of Psychiatry·Xulong WuLi Su
Oct 20, 2018·Analytical Chemistry·Chamari S WijesooriyaEmily A Smith
Sep 15, 2020·ACS Chemical Neuroscience·Daryl A GuthrieAmy Hauck Newman

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