Monday, October 7, 2024 10/7/2024

Mechanisms and Cellular Function of Opioid Receptor Endocytosis

Award Number: R01DA012864
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Opioid and catecholamine receptors are key regulators of neurophysiology and behavior, and are important targets of therapeutic and abused drugs. These receptors all belong to the G protein-coupled receptor (GPCR) superfamily, the largest group of signaling receptors expressed in animals and a very important class of drug targets. GPCRs signal by allostery and are extensively regulated after ligand-induced activation by phosphorylation, endocytosis and interacting with a class of cytoplasmic adaptor proteins called arrestins. These regulatory processes are critically important to the actions of addictive drugs, which are typically administered repeatedly or over a prolonged period, and there is evidence for considerable diversity of the effects of drugs on these processes. The present research program is focused on elucidating the fundamental mechanistic basis of such selective regulation. In the previous funding period, we delineated drug-selective biochemical modes by which a functionally relevant GPCR kinase is recruited from the cytoplasm by opioid receptors. We also identified evidence for a discrete form of biased drug action determined by differences in the subcellular location of receptor activation. We also discovered a distinct mechanism of cellular arrestin regulation that defined by being independent of receptor phosphorylation. The proposed studies seek to extend this fundamental research effort with the goal of developing new understanding that can be leveraged for therapeutic benefit. Specifically, we propose to (1) Define an allosteric basis for agonist-selective phosphorylation of opioid receptors; (2) Delineate localization and trafficking of opioid-relevant adenylyl cyclase isoforms; and (3) Determine if β-arrestin has a phosphorylation-independent role in opioid drug discrimination.


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: 2024 ( Subtotal = $376,575 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	001	23	4/26/2024	NON-COMPETING CONTINUATION	$37,658
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	23	2/22/2024	NON-COMPETING CONTINUATION	$338,917
														Subtotal = $376,575

Issue Date FY: 2023 ( Subtotal = $376,908 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	22	3/2/2023	NON-COMPETING CONTINUATION	$376,908
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	002	21	6/16/2023	COMPETING CONTINUATION	$54,763
2023	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	001	20	6/16/2023	NON-COMPETING CONTINUATION	-$54,763
														Subtotal = $376,908

Issue Date FY: 2022 ( Subtotal = $377,238 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	001	21	4/7/2022	COMPETING CONTINUATION	$377,238
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	20	4/1/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,238

Issue Date FY: 2020 ( Subtotal = $355,393 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	20	5/11/2020	NON-COMPETING CONTINUATION	$355,393
														Subtotal = $355,393

Issue Date FY: 2019 ( Subtotal = $354,593 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	19	5/28/2019	NON-COMPETING CONTINUATION	$354,593
														Subtotal = $354,593

Issue Date FY: 2018 ( Subtotal = $353,794 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	18	5/18/2018	NON-COMPETING CONTINUATION	$353,794
														Subtotal = $353,794

Issue Date FY: 2017 ( Subtotal = $352,994 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	17	5/24/2017	NON-COMPETING CONTINUATION	$352,994
														Subtotal = $352,994

Issue Date FY: 2016 ( Subtotal = $332,628 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	16	7/19/2016	COMPETING CONTINUATION	$332,628
														Subtotal = $332,628

Issue Date FY: 2015 ( Subtotal = $295,072 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	15	4/13/2015	NON-COMPETING CONTINUATION	$295,072
														Subtotal = $295,072

Issue Date FY: 2014 ( Subtotal = $299,567 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	14	4/14/2014	NON-COMPETING CONTINUATION	$299,567
														Subtotal = $299,567

Issue Date FY: 2013 ( Subtotal = $321,862 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	001	13	4/19/2013	NON-COMPETING CONTINUATION	$269,610
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	002	13	5/16/2013	NON-COMPETING CONTINUATION	$17,974
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	12	12/14/2012	SUPPLEMENT FOR EXPANSION	$34,278
														Subtotal = $321,862

Issue Date FY: 2012 ( Subtotal = $299,567 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	12	4/12/2012	NON-COMPETING CONTINUATION	$299,567
														Subtotal = $299,567

Issue Date FY: 2011 ( Subtotal = $299,567 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	11	7/15/2011	COMPETING CONTINUATION	$299,567
2011	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	001	10	7/15/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $299,567

Issue Date FY: 2010 ( Subtotal = $278,363 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	10	5/25/2010	NON-COMPETING CONTINUATION	$278,363
														Subtotal = $278,363

Issue Date FY: 2009 ( Subtotal = $281,175 )
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	9	6/30/2009	NON-COMPETING CONTINUATION	$281,175
														Subtotal = $281,175

Issue Date FY: 2008 ( Subtotal = $281,175 )
2008	2008	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	8	9/6/2008	NON-COMPETING CONTINUATION	$281,175
														Subtotal = $281,175

Issue Date FY: 2007 ( Subtotal = $285,984 )
2007	2007	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	7	6/29/2007	NON-COMPETING CONTINUATION	$285,984
														Subtotal = $285,984

Issue Date FY: 2006 ( Subtotal = $293,569 )
2006	2006	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	6	9/6/2006	COMPETING CONTINUATION	$293,569
														Subtotal = $293,569

Issue Date FY: 2004 ( Subtotal = $258,125 )
2004	2004	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	5	6/24/2004	NON-COMPETING CONTINUATION	$258,125
														Subtotal = $258,125

Issue Date FY: 2003 ( Subtotal = $258,125 )
2003	2003	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	4	6/26/2003	NON-COMPETING CONTINUATION	$258,125
														Subtotal = $258,125

Issue Date FY: 2002 ( Subtotal = $258,125 )
2002	2002	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Drug Abuse and Addiction Research Programs	000	3	6/14/2002	NON-COMPETING CONTINUATION	$258,125
														Subtotal = $258,125

Issue Date FY: 2001 ( Subtotal = $258,125 ) (Continued on the next page)
Grand Total All Awards = $7,106,649

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Mechanisms and Cellular Function of Opioid Receptor Endocytosis

Award Number: R01DA012864

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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