Tuesday, January 21, 2025 1/21/2025

The role of RGS12 in differential modulation of G protein versus beta-arrestin signaling downstream of the kappa opioid receptor

Award Number: R01DA048153
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The kappa opioid receptor (KOR) helps mediate responses to stress, yet is also implicated in developing and/or maintaining health disorders of chronic pain, drug addiction, anxiety and depression. KOR agonists have shown promise in ameliorating these disorders, but are limited by dysphoric side effects. Beneficial effects of KOR agonists (e.g., analgesia) are considered predominantly mediated by G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria). However, the mechanism(s) by which these signals downstream of KOR are regulated are still being elucidated. The Regulators of G protein Signaling are intracellular proteins that accelerate signal termination after G protein-coupled receptor activation. RGS12 is a complex member of this protein family, with at least five different domains that interact with components of both G protein-dependent and -independent signaling pathways. We recently reported that RGS12 is enriched in the ventral striatum (vSTR), and global Rgs12 ablation decreases locomotor responses to dopamine (DA)-modulating psychostimulants. Our data correlate with the augmented DA transporter (DAT) expression and function in the vSTR, but not dorsal striatum (dSTR), seen in RGS12-null mice. Loss of RGS12 (especially as a Gai/o-directed GTPase-accelerating protein) may indirectly increase DAT expression / function by removing negative regulation downstream of KOR, given that KOR agonists are known to increase DAT surface expression and uptake function. Supporting this notion, the augmented DAT function and reduced AMPH-stimulated locomotion caused by RGS12 loss are both reversed following KOR antagonism. We also found elevated KOR expression in the vSTR, but not dSTR, of RGS12-null and β-arrestin2-null mouse strains. RGS12 over-expression augments β-arrestin recruitment to activated KOR – an effect preserved following pertussis toxin-mediated Gi/o inhibition or mutation to the Ga-interacting domains of RGS12, suggesting a G protein-independent mechanism. These findings are consistent with our newest data that RGS12-null mice exhibit attenuated KOR agonist-induced conditioned place aversion, considered β-arrestin-dependent behavior. Collectively, our data highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation, a regulation that may be exploitable pharmacologically to help shift KOR-mediated signaling to beneficial outcomes and away from detrimental ones. Our first aim is to determine the specific neuronal populations within which RGS12 acts to modulate G protein- dependent and -independent KOR signaling, testing hypotheses that RGS12 operates to modulate KOR and DAT function specifically in KOR- and DAT- expressing CNS neurons, and also operates at the level of the spinal cord. Our second aim is to delineate the molecular determinants that engender selective functional interactions between RGS12 and KOR. Success in pursuit of these two aims will provide key pre-clinical data for considering RGS12 a valid target for future analgesic and anti-addiction therapeutics that engage KOR signal transduction.


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: 2025 ( Subtotal = $323,646 )
2025	2025	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	000	5	12/16/2024	NON-COMPETING CONTINUATION	$323,646
														Subtotal = $323,646

Issue Date FY: 2024 ( Subtotal = $359,673 )
2024	2024	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	000	4	12/8/2023	NON-COMPETING CONTINUATION	$323,705
2024	2024	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	001	4	4/29/2024	NON-COMPETING CONTINUATION	$35,968
														Subtotal = $359,673

Issue Date FY: 2023 ( Subtotal = $359,735 )
2023	2023	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	001	3	1/13/2023	NON-COMPETING CONTINUATION	$35,973
2023	2023	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	000	3	12/14/2022	NON-COMPETING CONTINUATION	$323,762
														Subtotal = $359,735

Issue Date FY: 2022 ( Subtotal = $359,793 )
2022	2022	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	001	2	3/25/2022	NON-COMPETING CONTINUATION	$35,981
2022	2022	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	000	2	12/7/2021	NON-COMPETING CONTINUATION	$323,812
														Subtotal = $359,793

Issue Date FY: 2021 ( Subtotal = $380,706 )
2021	2021	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Drug Use and Addiction Research Programs	000	1	2/10/2021	NEW	$380,706
														Subtotal = $380,706

Grand Total All Awards = $1,783,553

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The role of RGS12 in differential modulation of G protein versus beta-arrestin signaling downstream of the kappa opioid receptor

Award Number: R01DA048153

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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