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Dissecting G Protein Versus β-Arrestin–Mediated CB1 Receptor Signaling Pathways Using a Phosphorylation-Deficient CB1 Receptor

Award Number: R16GM165172
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Dissecting G Protein Versus β-Arrestin–Mediated CB1 Receptor Signaling Pathways Using a Phosphorylation-Deficient CB1 Receptor - Project Summary/Abstract Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor that is abundantly expressed in the central nervous system where it modulates key physiological functions including synaptic transmission, perception of pain, motor activity, appetite, and memory. Some CB1 agonists (nabilone and Δ9-tetrahydrocannabinol) have received Federal Drug Administration (FDA)-approval for the treatment of chemotherapy-induced nausea, cancer-associated pain, and neuropathic pain associated with multiple sclerosis. CB1 agonists are also being investigated for the treatment of epilepsy, ischemic stroke, Parkinson’s disease, traumatic brain injury, and other disorders. While CB1 agonists hold substantial therapeutic potential, the clinical use of CB1 agonists is often limited by adverse psychotropic effects, tolerance, and the development of dependence. CB1 primarily signals through Gαi-mediated inhibition of adenylyl cyclase but can also recruit β-arrestin following phosphorylation of its C-terminal tail by G protein-coupled receptor kinases (GRKs). β-arrestin mediates receptor desensitization, internalization, and activates distinct signaling pathways such as ERK and MAPK. Biased agonists that cause CB1 to selectively engage either G protein or β-arrestin signaling pathways (but not both) have the potential to separate therapeutic benefits from adverse effects, but the specific functional contributions of β-arrestin signaling (independent of G proteins) downstream of CB1 remain unclear. To address this, we developed a phosphorylation-deficient CB1 receptor (PD CB1) that cannot signal through β-arrestin but retains the ability to signal through G proteins. Mice and cell lines expressing PD CB1 provide new tools to enable β-arrestin– dependent signaling to be distinguished from G protein-dependent signaling. In Aim 1, we will test the hypothesis that β-arrestin-dependent signaling and G protein-dependent signaling activate spatially distinct (cytosolic vs. nuclear) pools of ERK. In Aim 2, we will determine how β-arrestin signaling contributes to acute and chronic behavioral responses to CB1 agonists using the cannabinoid tetrad assays in vivo. In Aim 3, we will determine whether loss of CB1 phosphorylation enhances CB1-D2 dopamine receptor dimerization and alters receptor signaling in vitro and behavior in vivo. This project will define key roles for β-arrestin in CB1 signaling and lay the groundwork for the development of biased CB1 ligands that signal either through G proteins or through β-arrestin (but not both) to maintain therapeutic efficacy while minimizing tolerance and adverse effects.


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 = $147,500 )
2026	2026	MARSHALL UNIVERSITY RESEARCH CORPORATION	1 JOHN MARSHALL DR	HUNTINGTON	WV	25755	CABELL	USA	Biomedical Research and Research Training	000	1	7/21/2026	NEW	$147,500
														Subtotal = $147,500

Grand Total All Awards = $147,500

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Dissecting G Protein Versus β-Arrestin–Mediated CB1 Receptor Signaling Pathways Using a Phosphorylation-Deficient CB1 Receptor

Award Number: R16GM165172

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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