Mechanisms of L-Type Calcium Channel Regulation in Heart Health and Disease

Grants and Contracts Details

Description

Inotropic support for hearts progressing towards failure represents an unmet need. Direct attempts to improve systolic function by activating β-adrenergic receptor (β-AR) signaling increases associated risk of heart failure and death. Calcitropes (agents influencing Ca2+ handling) that bypass β-AR signaling are not necessarily proarrhythmic. Our working global hypothesis based on our recent and ongoing work studying RAD regulation of the L-type Ca2+ channel (LTCC) is that bypassing β-AR signaling to increase Ca2+-induced Ca2+ release (CICR) provides safe, stable gain of function to counter heart failure progression. In this application we focus on the mechanisms of Rad – LTCC interactions as a novel means to instill inotropic support to the heart. The LTCC is a macromolecular hub that integrates multiple signaling pathways including protein kinase A (PKA) and Ca2+- calmodulin kinase II (CaMKII). RAD is a member of the RGK family of monomeric G-proteins. RAD binds to auxiliary CaVβ2 and CaV1.2, the pore-forming subunit of the LTCC. Deletion, or phosphorylation of RAD causes LTCC current (ICa,L) modulation and facilitation. Modulation of ICa,L is commonly observed after β-AR signaling to activate PKA; facilitation is caused by CaMKII activation. In Specific Aim 1 we will dissect how RAD integrates each of these signaling pathways using a combination of pharmacological and genetic approaches. In Specific Aim 2 we will explore RAD – CaV1.2 structure-function using knock-in models of genetically modified mice that allow us to explore RAD – LTCC effects retaining native stoichiometry of the LTCC heteromultimeric protein complex. Specific Aim 3 explores RAD – LTCC interplay as an approach to attenuate progression of heart failure. To achieve these goals, we will integrate findings among Aims using in vivo, ex vivo and cellular/molecular approaches in animal models. Ex vivo human heart slices will be tested to evaluate the translational potential of RAD – LTCC regulation in heart health and disease.
StatusActive
Effective start/end date7/31/235/31/27

Funding

  • National Heart Lung and Blood Institute: $1,261,616.00

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