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Regulation of ryanodine receptor 2 in the heart by phosphorylation at a novel site

Award Number: F31HL182146
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/07/2027
PERIOD OF PERFORMANCE END DATE: 01/06/2028

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Regulation of ryanodine receptor 2 in the heart by phosphorylation at a novel site - PROJECT SUMMARY Cardiac function relies on excitation-contraction (EC) coupling, the process that transduces electrical signals into mechanical force. Ryanodine receptor 2 (RyR2) is a key protein localized on the membrane surface of the intracellular Ca2+ store of the cardiomyocyte, the sarcoplasmic reticulum (SR). RyR2 releases Ca2+ from the SR and globally increases Ca2+ concentration to allow for cell contraction. As a critical modulator of this process, RyR2 function is strictly regulated. RyR2 forms complexes with other proteins, among them kinases. Phosphorylation of RyR2 channel by kinases like protein kinase A and calmodulin-dependent kinase II have been linked to physiological regulation of the channel as well as heart disease. Recent studies have revealed a new site for phosphorylation on RyR2 in a model of arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC is a progressive disease characterized by fibrofatty infiltrates that may lead to arrhythmia and sudden death. Mice with conditional knock-out of plakophilin 2 (PKP2cKO), the most commonly affected protein in ARVC patients, develop a disease consistent with ARVC in a compressed timeline, including a stage with electrical dysfunction without structural remodeling followed by overt cardiomyopathy. Cardiomyocytes from PKP2cKO mice display abnormal Ca2+ handling with a right-ventricle predominance. Noteworthy, unbiased mass spectrometry studies identified aberrant phosphorylation of RyR2 at a novel putative PKC site, T2810, similarly constrained to right ventricle myocytes. Treatment of RV myocytes with PKC inhibitors reduced Ca2+ mishandling, suggesting a link between PKC phosphorylation of RyR2 and Ca2+ mishandling in PKP2cKO cardiomyocytes. A clear definition of the role T2810 phosphorylation has on RyR2 regulation, both in the healthy and diseased heart, is needed to fill the evident void. Our lab generated two novel mice models containing a phospho-mimetic and phospho-ablation substitution of the T2810 residue (T2810D and T2810A, respectively). Our preliminary data suggests that phosphorylation of T2810 causes RyR2 channels to become hyperactive. Hence, I hypothesize phosphorylation at T2810 regulates RyR2 function. To test this, in Aim 1, I will investigate the direct role that T2810 phosphorylation plays on RyR2 function using molecular and cellular techniques on T2810A and T2810D mice. Additionally, our lab has generated a modified model of ARVC by crossing the conditional PKP2 knock-out mouse with the T2810A phospho-ablation mouse (PKP2cKO-T2810A). This prevents any phosphorylation event at this site in the ARVC model. Preliminary survival data shows that PKP2cKO-T2810A survive significantly longer than their PKP2cKO counterparts. In Aim 2, I will study the role of T2810 phosphorylation in ARVC development. I will monitor the progression of the disease using in vivo approaches while also characterizing the properties of Ca2+ handling in isolated cardiomyocytes. The data generated by the proposed research would provide insight into the regulation of RyR2 and open potential avenues for the development of therapeutics.


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 = $38,474 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	1	7/7/2026	NEW	$38,474
														Subtotal = $38,474

Grand Total All Awards = $38,474

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Regulation of ryanodine receptor 2 in the heart by phosphorylation at a novel site

Award Number: F31HL182146

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/07/2027

PERIOD OF PERFORMANCE END DATE: 01/06/2028

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