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Mechanisms of Cardiac Ryanodine Receptor Modulation by Phosphorylation

Award Number: R01HL055438
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Mechanisms of Cardiac Ryanodine Receptor Modulation by Phosphorylation The cardiac ryanodine receptor (RyR2) constitutes the main pathway for Ca2+ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling of the heart. The force of cardiac contraction is greatly dependent on the magnitude of Ca2+ release by RyR2 channels: during periods of stress or in the setting of exercise, ß-adrenergic stimulation of ventricular myocytes increases Ca2+ release and thus force of contraction. In isolated, beating hearts stimulated with ß-adrenergic agonists, RyR2 channels are among the first proteins to undergo metabolic phosphorylation. This suggests that RyR2 channels are an integral part of the concert of events by which ß-adrenergic receptors produce inotropic and lusitropic effects on the heart. Yet, the functional effect of RyR2 phosphorylation remains elusive. Wide ranges of importance have been attributed to RyR2 phosphorylation, from functionally inconsequential to a central mechanism in several cardiomyopathies. This proposal aims to elucidate the mechanisms underlying regulation of RyR2 by phosphorylation. We have gathered evidence to postulate that the present model of RyR2 phosphorylation, where one kinase (PKA or CaMKII) phosphorylates one RyR2 phosphoepitope (Ser2808 or Ser2814, respectively) and produces one discrete effect, is overly simplified and leads to erroneous assumptions. Instead, we propose a multi-site, bimodal and interactive model of RyR2 phosphorylation where Ser2808 and Ser2814 (and possibly Ser2811) all form part of a single signaling node (“phosphorylation hotspot”) that works in concert to modulate RyR2 gating in a graded manner. Our model also considers the emergent role of Ser2030, a PKA site, in the control of RyR2 modulation by phosphorylation, and the active contribution of protein phosphatases PP1 and PP2a to this process. We have generated key experimental animals and toolkits that will allow us to test with unprecedented integrative level the physiological and pathophysiological role of RyR2 phopshorylation and dephosphorylation in molecular, cellular, whole heart and intact animal settings. These studies are therefore likely to provide fresh, novel insight into the mechanisms that control RyR2 phosphorylation and the functional consequences of this process for the Ca2+ homeostasis of cardiac cells.


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: 2023 ( Subtotal = $546,478 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	25	3/21/2023	NON-COMPETING CONTINUATION	$546,478
														Subtotal = $546,478

Issue Date FY: 2022 ( Subtotal = $546,478 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	24	4/6/2022	NON-COMPETING CONTINUATION	$491,829
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	24	6/29/2022	NON-COMPETING CONTINUATION	$54,649
														Subtotal = $546,478

Issue Date FY: 2021 ( Subtotal = $546,099 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	002	23	4/21/2021	NON-COMPETING CONTINUATION	$546,099
2021	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	22	2/23/2021	COMPETING CONTINUATION	$1,421
2021	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	21	2/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,421
														Subtotal = $546,099

Issue Date FY: 2020 ( Subtotal = $558,713 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	22	3/31/2020	COMPETING CONTINUATION	$558,713
2020	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	21	3/23/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $558,713

Issue Date FY: 2018 ( Subtotal = $382,500 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	21	7/9/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$382,500
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	003	21	7/19/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,390
2018	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	002	20	7/19/2018	NON-COMPETING CONTINUATION	-$2,390
2018	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	20	7/7/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $382,500

Issue Date FY: 2017 ( Subtotal = $387,500 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	20	3/24/2017	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2016 ( Subtotal = $387,500 )
2016	2016	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	19	3/14/2016	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2015 ( Subtotal = $387,813 )
2015	2015	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	18	3/23/2015	COMPETING CONTINUATION	$387,813
														Subtotal = $387,813

Issue Date FY: 2013 ( Subtotal = $370,090 )
2013	2013	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	17	5/24/2013	NON-COMPETING CONTINUATION	$370,090
														Subtotal = $370,090

Issue Date FY: 2012 ( Subtotal = $388,750 )
2012	2012	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	16	7/29/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$388,750
2012	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	15	8/21/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $388,750

Issue Date FY: 2011 ( Subtotal = $367,370 )
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	15	6/1/2011	NON-COMPETING CONTINUATION	$367,370
														Subtotal = $367,370

Issue Date FY: 2010 ( Subtotal = $367,370 )
2010	2010	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	14	4/5/2010	NON-COMPETING CONTINUATION	$367,370
2010	2010	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	14	5/14/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $367,370

Issue Date FY: 2009 ( Subtotal = $367,370 )
2009	2009	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	002	13	7/8/2009	COMPETING CONTINUATION	$367,370
2009	2007	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	12	2/9/2009	NON-COMPETING CONTINUATION	$0
2009	2007	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	001	12	7/8/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $367,370

Issue Date FY: 2007 ( Subtotal = $307,936 )
2007	2007	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	12	8/25/2007	NON-COMPETING CONTINUATION	$307,936
														Subtotal = $307,936

Issue Date FY: 2006 ( Subtotal = $317,207 )
2006	2006	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Cardiovascular Diseases Research	000	11	8/25/2006	NON-COMPETING CONTINUATION	$317,207
														Subtotal = $317,207

Issue Date FY: 2005 ( Subtotal = $393,635 )
2005	2005	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Cardiovascular Diseases Research	000	10	8/16/2005	NON-COMPETING CONTINUATION	$367,020
2005	2005	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Cardiovascular Diseases Research	001	9	2/18/2005	SUPPLEMENT FOR EXPANSION	$26,615
														Subtotal = $393,635

Issue Date FY: 2004 ( Subtotal = $324,986 )
2004	2004	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Cardiovascular Diseases Research	000	9	8/6/2004	COMPETING CONTINUATION	$324,986
														Subtotal = $324,986

Issue Date FY: 2003 ( Subtotal = $252,000 )
2003	2003	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Cardiovascular Diseases Research	000	8	8/18/2003	NON-COMPETING CONTINUATION	$252,000
														Subtotal = $252,000

Issue Date FY: 2002 ( Subtotal = $252,000 )
2002	2002	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Cardiovascular Diseases Research	000	7	8/1/2002	NON-COMPETING CONTINUATION	$252,000
														Subtotal = $252,000

Grand Total All Awards = $8,248,227

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Mechanisms of Cardiac Ryanodine Receptor Modulation by Phosphorylation

Award Number: R01HL055438

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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