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cAMP Compartmentation in Cardiac Myocytes

Award Number: R01HL145778
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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cAMP Compartmentation in Cardiac Myocytes - The cAMP signaling pathway plays a critical role in regulating many different aspects of cardiac myocyte function, including gene transcription, cell metabolism, and excitation-contraction coupling. However, not all G-protein coupled receptors that stimulate cAMP production produce the same responses. Subcellular compartmentation of cAMP is essential to explain how different receptors can utilize the same diffusible second messenger to elicit unique functional responses. Furthermore, disruption of cAMP compartmentation has been linked to various disease states, including cardiac hypertrophy, heart failure, and arrhythmias. Yet, a complete picture of the mechanisms contributing to cAMP compartmentation remains a mystery. Most work has focused on the role of phosphodiesterases (PDEs), which breakdown cAMP and are commonly thought to act as either functional barriers or active sinks that define different signaling domains. However, a number of studies indicate that PDE activity alone is not sufficient. The results suggest that, in addition to PDE activity, unique receptor-dependent responses can only be explained if the movement of intracellular cAMP is somehow limited by other mechanisms. Using a sophisticated new approach, we have directly measured the diffusion coefficient of cAMP in intact myocytes and found that it does indeed move dramatically slower than previously thought. Furthermore, our preliminary data have identified two factors critical to explaining this behavior. The first is buffering of cAMP by protein kinase A (PKA) immobilized by A kinase anchoring proteins (AKAPs). The second are subcellular restricted spaces. In this proposal, we will address the following specific questions: 1) Does buffering by PKA anchored to the outer membrane of mitochondria contribute to cAMP compartmentation? and 2) Does the restricted space associated with dyadic clefts contribute to cAMP compartmentation. To answer these questions, we will use a combination of molecular, biochemical, and biophysical techniques. These include raster image correlation spectroscopy (RICS) to directly measure cAMP diffusion, fluorescence resonance energy transfer (FRET)-based biosensors targeted to different subcellular locations to measure cAMP compartmentation; and patch clamp electrophysiology, Ca2+ fluorometry, and myocyte shortening to measure compartmentalized cAMP-dependent functional responses. The answers to these questions could lead to the development of novel approaches to halting the progression of cardiovascular disease and preventing the deadly consequences.


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 = $0 )
2025	2022	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	000	4	4/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	000	4	12/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $360,000 )
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	001	4	6/8/2022	NON-COMPETING CONTINUATION	$36,000
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	000	4	12/20/2021	NON-COMPETING CONTINUATION	$324,000
														Subtotal = $360,000

Issue Date FY: 2021 ( Subtotal = $360,000 )
2021	2021	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	001	3	5/24/2021	NON-COMPETING CONTINUATION	$36,000
2021	2021	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	000	3	12/24/2020	NON-COMPETING CONTINUATION	$324,000
														Subtotal = $360,000

Issue Date FY: 2020 ( Subtotal = $360,000 )
2020	2020	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	000	2	1/2/2020	NON-COMPETING CONTINUATION	$342,000
2020	2020	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$18,000
														Subtotal = $360,000

Issue Date FY: 2019 ( Subtotal = $360,000 )
2019	2019	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Cardiovascular Diseases Research	000	1	1/13/2019	NEW	$360,000
														Subtotal = $360,000

Grand Total All Awards = $1,440,000

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cAMP Compartmentation in Cardiac Myocytes

Award Number: R01HL145778

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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