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Regulation of Dopamine Transporter by Trafficking

Award Number: R01DA014204
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2001
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Regulation of Dopamine Transporter by Trafficking - Plasma membrane dopamine (DA) transporter (DAT) is expressed exclusively in dopaminergic neurons and serves for the reuptake of extracellular DA into these neurons to limit the duration and amplitude of DA signaling in the brain. DAT is a primary target of addictive psychostimulants such as cocaine and amphetamines. DAT expression levels at the plasma membrane of synaptic areas of striatal DA axons is the major determinant of extracellular DA concentrations, and these levels are defined by membrane trafficking. However, mechanisms by which proper distribution of DAT within the neuron and its membrane compartments is controlled by trafficking, how intracellular signaling regulates this trafficking and how abused psychostimulants affect DAT traffic in vivo remain poorly understood. The fundamental goal of our research is to define how intracellular trafficking regulates DAT function. During the last cycle of this program, we described the kinetics and mechanisms of the “long-distance” DAT traffic between midbrain and striatum through the medial forebrain bundle axons using HA-epitope tagged DAT (HA-DAT) knock-in mice that we have previously generated. Analysis of HA-DAT trafficking in intact mouse brain was enabled by the development of a novel HA-DAT endocytosis assay using stereotactic injections of HA antibodies. We have also discovered dramatic down-regulation of DAT in the striatum of amphetamine-sensitized male but not female mice, with the strongest amphetamine effects observed in nucleus accumbens. We identified small-molecule compounds that stabilize DAT oligomers and cause robust DAT endocytosis with remarkable specificity to DAT, which led to the demonstration of the coupling of DAT molecular mechanics and substrate- transport activity with its oligomerization and endocytosis. Based on these studies, we hypothesize that an inward-facing (IF) conformation of DAT induced by amphetamine favors DAT endocytosis. Generation of new DAT mutants led to hypothesis that a PDZ domain protein mediates protein kinase C dependent ubiquitination and endocytosis of DAT. Development of the DAT fusion protein with ascorbate peroxidase (APEX2) and demonstration of the feasibility of tracking the temporally resolved proximity proteome of APEX2-DAT opened new avenues for defining DAT interactome in specific brain regions and in animals treated with amphetamine, which will be indispensable for studying mechanisms involved in DAT regulation in vivo. We will pursue our comprehensive analysis of DAT trafficking and function by: 1) defining the molecular mechanisms of drug- and stimuli-induced endocytosis of DAT using heterologous cells and DA neurons; 2) elucidating the mechanisms underlying down-regulation of DAT in response to amphetamine challenge of amphetamine-sensitized mice and sex-dependence of this response; 3) defining the brain-region-specific proximity proteome of DAT in mouse brain using APEX2-based biotin labeling combined with quantitative mass-spectrometry and analyzing putative DAT interactors and regulators.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $394,340 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	23	6/26/2026	NON-COMPETING CONTINUATION	$394,340
														Subtotal = $394,340

Issue Date FY: 2025 ( Subtotal = $424,373 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Drug Use and Addiction Research Programs	001	22	5/19/2025	NON-COMPETING CONTINUATION	$424,373
2025	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	19	2/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $424,373

Issue Date FY: 2024 ( Subtotal = $424,572 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	21	6/28/2024	NON-COMPETING CONTINUATION	$424,572
														Subtotal = $424,572

Issue Date FY: 2023 ( Subtotal = $448,552 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	20	7/31/2023	COMPETING CONTINUATION	$448,552
														Subtotal = $448,552

Issue Date FY: 2021 ( Subtotal = $385,678 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	19	6/18/2021	NON-COMPETING CONTINUATION	$385,678
														Subtotal = $385,678

Issue Date FY: 2020 ( Subtotal = $394,444 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	18	6/17/2020	NON-COMPETING CONTINUATION	$394,444
														Subtotal = $394,444

Issue Date FY: 2019 ( Subtotal = $403,206 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	17	6/27/2019	NON-COMPETING CONTINUATION	$403,206
														Subtotal = $403,206

Issue Date FY: 2018 ( Subtotal = $444,248 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	16	6/11/2018	NON-COMPETING CONTINUATION	$444,248
														Subtotal = $444,248

Issue Date FY: 2017 ( Subtotal = $452,999 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	15	9/6/2017	COMPETING CONTINUATION	$452,999
2017	2015	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	001	14	9/15/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $452,999

Issue Date FY: 2015 ( Subtotal = $336,526 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	14	4/23/2015	NON-COMPETING CONTINUATION	$336,526
														Subtotal = $336,526

Issue Date FY: 2014 ( Subtotal = $338,050 )
2014	2014	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	13	4/4/2014	NON-COMPETING CONTINUATION	$338,050
														Subtotal = $338,050

Issue Date FY: 2013 ( Subtotal = $327,984 )
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	001	12	5/16/2013	NON-COMPETING CONTINUATION	$20,499
2013	2013	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	12	4/18/2013	NON-COMPETING CONTINUATION	$307,485
														Subtotal = $327,984

Issue Date FY: 2012 ( Subtotal = $360,783 )
2012	2012	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	11	4/25/2012	NON-COMPETING CONTINUATION	$360,783
														Subtotal = $360,783

Issue Date FY: 2011 ( Subtotal = $341,932 )
2011	2011	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	001	10	7/5/2011	COMPETING CONTINUATION	$341,932
2011	2010	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	000	9	6/30/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $341,932

Issue Date FY: 2010 ( Subtotal = $321,127 )
2010	2010	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Drug Use and Addiction Research Programs	001	9	3/17/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$321,127
2010	2009	UNIVERSITY OF COLORADO DENVER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	8	3/17/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $321,127

Issue Date FY: 2009 ( Subtotal = $323,520 )
2009	2009	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	8	4/17/2009	NON-COMPETING CONTINUATION	$323,520
														Subtotal = $323,520

Issue Date FY: 2008 ( Subtotal = $323,758 )
2008	2008	UNIVERSITY OF COLORADO DENVER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	7	3/31/2008	NON-COMPETING CONTINUATION	$323,758
														Subtotal = $323,758

Issue Date FY: 2007 ( Subtotal = $328,947 )
2007	2007	UNIVERSITY OF COLORADO HEALTH SCIENCES CENTER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	6	4/2/2007	NON-COMPETING CONTINUATION	$328,947
														Subtotal = $328,947

Issue Date FY: 2006 ( Subtotal = $339,004 )
2006	2006	UNIVERSITY OF COLORADO HEALTH SCIENCES CENTER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	5	2/23/2006	COMPETING CONTINUATION	$339,004
														Subtotal = $339,004

Issue Date FY: 2004 ( Subtotal = $295,466 )
2004	2004	UNIV OF COLORADO HEALTH SCIENCE CTR	PO BOX 6508 MAIL STOP F428	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	4	3/4/2004	NON-COMPETING CONTINUATION	$295,466
														Subtotal = $295,466

Issue Date FY: 2003 ( Subtotal = $295,717 )
2003	2003	UNIV OF COLORADO HEALTH SCIENCE CTR	PO BOX 6508 MAIL STOP F428	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	3		NON-COMPETING CONTINUATION	$295,717
														Subtotal = $295,717

Issue Date FY: 2002 ( Subtotal = $295,959 )
2002	2002	UNIV OF COLORADO HEALTH SCIENCE CTR	PO BOX 6508 MAIL STOP F428	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	2	3/20/2002	NON-COMPETING CONTINUATION	$295,959
														Subtotal = $295,959

Issue Date FY: 2001 ( Subtotal = $296,191 ) (Continued on the next page)
Grand Total All Awards = $8,297,376

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Regulation of Dopamine Transporter by Trafficking

Award Number: R01DA014204

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2001

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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