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Phosphodiesterases govern nuclear cAMP signaling for gene expression

Award Number: R01MH134119
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Phosphodiesterases govern nuclear cAMP signaling for gene expression - Abstract Studies have established the critical roles of a superfamily of phosphodiesterases (PDEs) in hydrolyzing cAMP and its subcellular distribution. We aim to explore the role of PDEs in differential regulation of the cAMP signals at the plasma membrane and in the nucleus. Specifically, we will uncover the regulation of the nuclear cAMP signals under the CNS β2-adrenergic receptor (b2AR) stimulation in hippocampal (HC) neurons during learning and memory. Interestingly, PDE4 inhibitors benefit learning and memory in rodents and humans, indicating that PDE4 may control the βAR-induced cAMP signal in the nucleus. PDE4D isoforms are associated with β2AR to fine-tune subcellular cAMP-PKA signals in fibroblasts and myocytes, and PDE4D5 is associated with an AKAP95/PKA complex in the nucleus. Our preliminary data show that βAR stimulation promotes the nuclear export of PDE4D5 in HC neurons. This relocation of PDE4D5 depends on endosome GRK-phosphorylated b2AR and is critically necessary for delivering cAMP signals into the nucleus. Besides the GRK-phosphorylated b2AR, we have recently characterized another distinct subpopulation of b2AR that are PKA-phosphorylated and located at the PM after agonist stimulation in HC neurons. We hypothesize that two b2AR subpopulations synergistically promote nuclear cAMP signal by arrestin3-dependent export of PDE4D5 from the nucleus. We will characterize the mechanisms underlying the PDE4D5-dependent regulation of nuclear cAMP signaling and gene expression and how the regulation may affect the b2AR signaling in learning and memory (Aim 3). This proposed study will define the role of PDE4D5 in nuclear cAMP signaling, gene expression, and learning and memory, which not only offer new strategies to treat disorders associated with the CNS adrenergic system but also offer an example to study many other Gs-coupled receptors, such as dopamine receptors in the regulation of gene expression.


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 = $607,600 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Mental Health Research Grants	000	4	6/17/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$607,600
														Subtotal = $607,600

Issue Date FY: 2025 ( Subtotal = $716,027 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	003	3	9/23/2025	SUPPLEMENT FOR EXPANSION	$94,924
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	001	3	6/13/2025	NON-COMPETING CONTINUATION	$621,103
2025	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	002	2	7/15/2025	OTHER REVISION	$0
2025	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	2	4/28/2025	TERMINATION	$0
														Subtotal = $716,027

Issue Date FY: 2024 ( Subtotal = $700,140 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	001	2	7/25/2024	SUPPLEMENT FOR EXPANSION	$79,037
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	2	5/13/2024	NON-COMPETING CONTINUATION	$621,103
														Subtotal = $700,140

Issue Date FY: 2023 ( Subtotal = $617,727 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	1	8/7/2023	NEW	$617,727
														Subtotal = $617,727

Grand Total All Awards = $2,641,494

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Phosphodiesterases govern nuclear cAMP signaling for gene expression

Award Number: R01MH134119

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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