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Fight-or-flight responses require augmentation of Ca2+ influx via Rad phosphorylation

ABSTRACT: Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. Despite decades of investigations, predominantly focusing on ryanodine receptor and phospholamban phosphorylation, the molecular mechanisms underlying the sympathetic nervous system control of cardiac contractility remain controversial and incompletely elucidated. Here, we identify the calcium-channel inhibitor Rad as a critical component. In cardiomyocytes isolated from knock-in mice expressing Rad with alanine-substitutions of the four PKA-phosphorylated serine residues (4SA-Rad), calcium currents cannot be increased by adrenergic agonists or phosphatase inhibitor. In these mice, basal cardiac contractility, exercise capacity and heart rate are reduced, and the augmentation of contractile force by adrenergic agonists is severely blunted. Expression of mutant calcium-channel β-subunits that cannot bind Rad is sufficient to restore calcium influx and cardiac contractility in 4SA-Rad mice to levels induced by adrenergic agonists in wild-type mice, revealing a potential therapeutic approach to enhance cardiac contractility while bypassing stimulation of adrenergic receptors.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Gary Bradshaw

LAB HEAD: Steven O. Marx

PROVIDER: PXD033492 | Pride | 2022-09-26

REPOSITORIES: Pride

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			Action	DRS
	513568_newsearch_GL_pulldown_15plex_July2021_Fr1_11572.mzIdentML	Mzid
	513570_newsearch_GL_pulldown_15plex_July2021_Fr2_11573.mzIdentML	Mzid
	513572_newsearch_GL_pulldown_15plex_July2021_Fr2_rerun_11579.mzIdentML	Mzid
	513574_newsearch_GL_pulldown_15plex_July2021_Fr3_11574.mzIdentML	Mzid
	513576_newsearch_GL_pulldown_15plex_July2021_Fr4_11575.mzIdentML	Mzid

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Project description:This a model from the article: Modeling beta-adrenergic control of cardiac myocyte contractility in silico. Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD. J Biol Chem 2003 Nov 28;278(48):47997-8003 12972422 , Abstract: The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD. (2003) - version=1.0 The original CellML model was created by: Geoffrey Nunns gnunns1@jhu.edu The University of Auckland This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Fight-or-flight responses require augmentation of Ca2+ influx via Rad phosphorylation

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