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

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $617,878

## Abstract

Inotropic support for hearts progressing towards failure represents an unmet need. Direct attempts to improve
systolic function by activating -adrenergic receptor (-AR) signaling increases associated risk of heart failure
and death. Calcitropes (agents influencing Ca2+ handling) that bypass -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 -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 CaV2 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 -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.

## Key facts

- **NIH application ID:** 10896208
- **Project number:** 5R01HL166280-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Jonathan Satin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $617,878
- **Award type:** 5
- **Project period:** 2023-07-31 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896208

## Citation

> US National Institutes of Health, RePORTER application 10896208, Mechanisms of L-type Calcium Channel Regulation in Heart Health and Disease (5R01HL166280-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10896208. Licensed CC0.

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