scholarly journals Mutational effects of human dopamine transporter at tyrosine88, lysine92, and histidine547 on basal and HIV-1 Tat-inhibited dopamine transport

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wei-Lun Sun ◽  
Pamela M. Quizon ◽  
Yaxia Yuan ◽  
Matthew J. Strauss ◽  
Richard McCain ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Dopamine Transport ◽  
Hiv 1

scholarly journals Mutations of Human DopamineTransporter at Tyrosine88, Aspartic Acid206, and Histidine547 Influence Basal and HIV-1 Tat‐inhibited Dopamine Transport

2021 ◽  
Author(s):  
Pamela M. Quizon ◽  
Yaxia Yuan ◽  
Yike Zhu ◽  
Yi Zhou ◽  
Matthew J. Strauss ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Inhibitory Effect ◽  
Conformational State ◽  
Dopamine Uptake ◽  
Maximal Velocity ◽  
Wild Type ◽  
Allosteric Interaction ◽  
Dopamine Transport ◽  
Transactivator Of Transcription ◽  
Hiv 1

AbstractHIV-1 transactivator of transcription (Tat) has a great impact on the development of HIV-1 associated neurocognitive disorders through disrupting dopamine transmission. This study determined the mutational effects of human dopamine transporter (hDAT) on basal and Tat-induced inhibition of dopamine transport. Compared to wild-type hDAT, the maximal velocity (Vmax) of [3H]dopamine uptake was decreased in D381L and Y88F/D206L/H547A, increased in D206L/H547A, and unaltered in D206L. Recombinant TatR1 − 86 inhibited dopamine uptake in wild-type hDAT, which was attenuated in either DAT mutants (D206L, D206L/H547A, and Y88F/D206L/H547A) or mutated TatR1 − 86 (K19A and C22G), demonstrating perturbed Tat-DAT interaction. Mutational effects of hDAT on the transporter conformation were evidenced by attenuation of zinc-induced increased [3H]WIN35,428 binding in D206L/H547A and Y88F/D206A/H547A and enhanced basal MPP+ efflux in D206L/H547A. H547A-induced outward-open transport conformational state was further validated by enhanced accessibility to MTSET ([2-(trimethylammonium)ethyl]-methanethiosulfonate) of an inserted cysteine (I159C) on a hDAT background.. Furthermore, H547A displayed an increase in palmitoylation inhibitor-induced inhibition of dopamine uptake relative to wide-type hDAT, indicating a change in basal palmitoylation in H547A. These results demonstrate that Y88F, D206L, and H547A attenuate Tat inhibition while preserving DA uptake, providing insights into identifying targets for improving DAT-mediated dopaminergic dysregulation. Graphical Abstract HIV-1 Tat inhibits dopamine uptake through human dopamine transporter (hDAT) on the presynaptic terminal through a direct allosteric interaction. Key hDAT residues D-H547, D-Y88, and D-D206 are predicted to be involved in the HIV-1 Tat-DAT binding. Mutating these residues attenuates this inhibitory effect by disrupting the Tat-hDAT interaction

scholarly journals Mutations at Tyrosine 88, Lysine 92 and Tyrosine 470 of Human Dopamine Transporter Result in an Attenuation of HIV-1 Tat-Induced Inhibition of Dopamine Transport

2015 ◽  
Vol 10 (1) ◽  
pp. 122-135 ◽  
Author(s):  
Narasimha M. Midde ◽  
Yaxia Yuan ◽  
Pamela M. Quizon ◽  
Wei-Lun Sun ◽  
Xiaoqin Huang ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Dopamine Transport ◽  
Hiv 1

scholarly journals Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Pamela M. Quizon ◽  
Wei-Lun Sun ◽  
Yaxia Yuan ◽  
Narasimha M. Midde ◽  
Chang-Guo Zhan ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Dopamine Transporter ◽  
Tat Protein ◽  
Dopamine Transport ◽  
Hiv 1

scholarly journals Mutation of Tyrosine 470 of Human Dopamine Transporter is Critical for HIV-1 Tat-Induced Inhibition of Dopamine Transport and Transporter Conformational Transitions

2013 ◽  
Vol 8 (4) ◽  
pp. 975-987 ◽  
Author(s):  
Narasimha M. Midde ◽  
Xiaoqin Huang ◽  
Adrian M. Gomez ◽  
Rosemarie M. Booze ◽  
Chang-Guo Zhan ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Conformational Transitions ◽  
Dopamine Transport ◽  
Hiv 1

scholarly journals Molecular Mechanism of Dopamine Transport by Human Dopamine Transporter

Structure ◽  
2015 ◽  
Vol 23 (11) ◽  
pp. 2171-2181 ◽  
Author(s):  
Mary Hongying Cheng ◽  
Ivet Bahar
Keyword(s):  
Molecular Mechanism ◽  
Dopamine Transporter ◽  
Dopamine Transport

scholarly journals Dopamine transporter phosphorylation site threonine 53 is stimulated by amphetamines and regulates dopamine transport, efflux, and cocaine analog binding

2017 ◽  
Vol 292 (46) ◽  
pp. 19066-19075 ◽  
Author(s):  
Sathya Challasivakanaka ◽  
Juan Zhen ◽  
Margaret E. Smith ◽  
Maarten E. A. Reith ◽  
James D. Foster ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Phosphorylation Site ◽  
Dopamine Transport

scholarly journals Molecular Mechanism of HIV-1 Tat Interacting with Human Dopamine Transporter

2015 ◽  
Vol 6 (4) ◽  
pp. 658-665 ◽  
Author(s):  
Yaxia Yuan ◽  
Xiaoqin Huang ◽  
Narasimha M. Midde ◽  
Pamela M. Quizon ◽  
Wei-Lun Sun ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Dopamine Transporter ◽  
Hiv 1

The dopamine transporter counter-transports potassium to increase the uptake of dopamine

2021 ◽  
Author(s):  
Claus Loland ◽  
Solveig Schmidt ◽  
Mette Malle ◽  
Anne Nielsen ◽  
Søren Bohr ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Dopamine Transporter ◽  
Conformational Dynamics ◽  
Common Mechanism ◽  
Coupled Transport ◽  
Gaba A ◽  
Dopamine Reuptake ◽  
Dopamine Transport ◽  
Neurotransmitter:Sodium Symporter ◽  
The Impact

Abstract The dopamine transporter (DAT) facilitates dopamine reuptake from the extracellular space, and thereby terminates neurotransmission and refills cellular stores of dopamine. DAT belongs to the neurotransmitter:sodium symporter (NSS) family, which includes similar transporters for serotonin, norepinephrine, and GABA. A hallmark of NSS proteins is their ability to utilize the energy stored in the inward-directed Na+ gradient to drive the uphill transport of substrate. Decades ago, it was shown that the serotonin transporter also counter-transports K+, but investigations of K+-coupled transport in other NSSs have been inconclusive. Here, we show that the Drosophila dopamine transporter (dDAT) counter-transports K+. We found that ligand binding to both dDAT and human DAT is inhibited by K+ and that the conformational dynamics of dDAT in K+ is highly divergent from both the apo- and Na+-bound conformations. Furthermore, we found that K+ increased dopamine uptake by purified dDAT reconstituted in liposomes, and we visualized, in real-time, Na+ and K+ fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K+ on other NSSs, including whether K+ counter-transport is a common mechanism for this pharmacologically important protein family.

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