# Elucidating the mechanism of beta-adrenergic regulation in L-type Calcium Channels (CaV1.2)

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $6,800

## Abstract

Project Summary
 My overall goal is to uncover mechanisms responsible for physiological regulation of the voltage-gated
calcium channel in the heart. Calcium influx through voltage-gated L-type calcium channels (CaV1.2) is an
essential signal initiating each heartbeat. Dysfunctional calcium channel trafficking and regulation have been
implicated in the mechanisms of arrhythmias, cardiac hypertrophy, and heart failure. During the “fight or flight”
response, beta-adrenergic activation of protein kinase A (PKA) increases this calcium influx and increases
cardiac contractility. Despite decades of investigation, the detailed mechanism by which this pathway activates
calcium channels in the heart remains unknown. Strong preliminary data in the laboratory suggest that the
calcium channel inhibitor Rad, a small G-protein, is the missing link that enables PKA regulation of CaV1.2.
Based on proximity proteomics, Rad is enriched in the CaV1.2 microenvironment but is depleted during beta-
adrenergic stimulation in the heart. We confirmed in a heterologous expression system that Rad co-expression
fully-reconstituted PKA modulation at the whole-cell level and recapitulated single-channel characteristics of PKA
modulation. Furthermore, we demonstrated that Rad is also the key functional target of PKA phosphorylation,
as eliminating Rad phosphorylation sites abolished forskolin-mediated stimulation of the calcium channels. In
the end, the underlying mechanism turns out to be simple and elegant – Rad at baseline inhibits CaV1.2 activity,
while PKA phosphorylation of Rad relieves this inhibition. My hypothesis is that Rad phosphorylation is sufficient
for calcium channel regulation in the heart, and that loss of beta-adrenergic regulation of calcium channels
attenuates adrenergic-induced increase in inotropy.
essential component of beta-adrenergic regulation,
Via two Aims, I will: (1) validate Rad phosphorylation as an
and (2) assess the contribution of PKA-induced stimulation
of calcium currents in forming the cardiac response to beta-adrenergic agonists. Both Aims utilize novel knock-
in mice, and require cellular electrophysiological techniques and in vivo measurements of cardiac function. The
two Aims will identify new mechanisms responsible for regulation of calcium influx in cardiomyocytes, which may
lead to novel approaches to modulate cardiac contractility and arrhythmias.

## Key facts

- **NIH application ID:** 10490970
- **Project number:** 5F31HL158232-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Arianne Papa
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $6,800
- **Award type:** 5
- **Project period:** 2021-06-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490970

## Citation

> US National Institutes of Health, RePORTER application 10490970, Elucidating the mechanism of beta-adrenergic regulation in L-type Calcium Channels (CaV1.2) (5F31HL158232-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10490970. Licensed CC0.

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