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Role of S-nitrosylated Cx43 in normal cardiac contractility

Award Number: R21HL163930
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Role of S-nitrosylated Cx43 in normal cardiac contractility - Modulation of cardiac function by sympathetic activity, which occurs during exercise and emotional excitement, is thought to promote an augmentation of cell-to-cell electrical coupling in the heart. This is necessary to increase the strength of cardiac muscle contraction. Electrical coupling in the heart is mediated by specialized structures at the intercalated discs of cardiomyocytes, referred to as gap junction channels (GJCs). These are intercellular channels formed by connexin proteins, with connexin 43 (Cx43) being the most abundant in the heart. While is known that Cx43 GJCs are vital to sustain the propagation of electrical impulses and coordinated heart contraction, the mechanisms by which cardiac GJC coupling is regulated remains poorly understood. It has recently been proposed that β-adrenergic stimulation, which is used to mimic sympathetic activity, induces nitric oxide (NO) production and S-nitrosylation of cardiac proteins and this may account for one third of the inotropic effects in the heart. In this context, we found Cx43 at the intercalated disk is heavily S-nitrosylated upon β-adrenergic stimulation. In addition, we found that NO increases coupling mediated by Cx43 GJCs in a heterologous expression system. Accordingly, we hypothesize that S-nitrosylated Cx43 GJCs enhances electrical coupling between cardiomyocytes, which is critical for concerted contractility. To test our hypothesis, we identified the S-nitrosylated site and created a knockin mouse line where this site (C271) was replaced by a serine, and which we will use to assess cardiac function in vivo. In addition, we will perform biophysical studies to unveil the molecular mechanisms by which NO induce increased GJC coupling in the cardiomyocytes. The proposed research is innovative, as it is designed to reveal novel biophysical properties of S-nitrosylated Cx43 GJCs and provide mechanistic understanding on cardiac conduction and contractility.


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 = $0 )
2024	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cardiovascular Diseases Research	000	2	7/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $198,714 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cardiovascular Diseases Research	000	2	3/21/2023	NON-COMPETING CONTINUATION	$198,714
														Subtotal = $198,714

Issue Date FY: 2022 ( Subtotal = $252,079 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cardiovascular Diseases Research	000	1	3/31/2022	NEW	$252,079
														Subtotal = $252,079

Grand Total All Awards = $450,793

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Role of S-nitrosylated Cx43 in normal cardiac contractility

Award Number: R21HL163930

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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