# Molecular choreography of CaV1.2 channels in the aging myocardium

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $321,850

## Abstract

Project Summary
 Experiments outlined in this application, suggest a novel paradigm, in which we add a new layer of complexity
to the current understanding of β-adrenergic receptor (βAR)-mediated regulation of CaV1.2 channels and EC-
coupling. We propose that stimulation of βARs initiates dynamic augmention of CaV1.2 channel abundance,
enhanced cooperative gating of CaV1.2 channels, and de novo couplon formation in the sarcolemma of young
ventricular myocytes, to amplify Ca2+ influx into these cells and tune EC-coupling in times of high demand. Our
preliminary data suggest that a pre-synthesized pool of sub-sarcolemmal, CaV1.2 channels-containing
vesicles/endosomes, resides in cardiomyocytes and can be mobilized to the sarcolemma in times of high
metabolic or hemodynamic demand. We hypothesize that insertion of these ‘new’ channels into the sarcolemma
occurs in a PKA- and CaMKII-mediated phosphyorylation dependent fashion, while subsequent internalization
of the mobile pool when demand decreases, occurs in a CaN-mediated dephosphorylation dependent manner.
Further preliminary data suggests that the BAR-domain containing protein BIN1, choreographs this response,
with roles in microtubule and actin mediated CaV1.2 targeting to the sarcolemma and in trafficking channels out
of early endosomes and recycling them back to the cell surface. Strikingly, this dynamic regulatory process is
absent in ventricular myocytes isolated from aged mice where we find cardiac BIN1 protein levels are almost
doubled. Increased expression of BIN1 in the brain with aging is associated with Alzheimer’s Disease and defects
in intracellular trafficking termed ‘endosomal traffic jams’. We hypothesize that increased levels of BIN1 with
aging, could cause analogous endosomal traffic jams in ventricular myocytes, leading to enhanced basal CaV1.2
expression at the sarcolemma and depletion of the readily insertable pool of channels. We propose a model in
which BIN1 acts as a hub for CaV1.2 channel delivery to the sarcolemma in ventricular myocytes, and suggest
that altered distribution and activity of CaV1.2 channels, and reduced responsivity to βAR stimulation with aging
is mediated by changes in BIN1 expression. Specific Aim 1 tests the hypothesis that βAR activation stimulates
age-dependent dynamic augmentation of sarcolemmal CaV1.2 channel abundance and clustering. Specific Aim
2 tests the hypothesis that changes in BIN1 expression underlie the altered dynamics and retention of CaV1.2
channels with aging. Finally, specific Aim 3 tests the hypothesis that age-related differences in CaV1.2 channel
dynamics and trafficking in ventricular myocytes leads to impaired EC-coupling during the ‘fight or flight’
response. To achieve these aims, we employ a multi-faceted approach using state-of-the-art methods and
analyses including super-resolution imaging, patch clamp electrophysiology, TIRF and confocal imaging

## Key facts

- **NIH application ID:** 10617814
- **Project number:** 5R01AG063796-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Rose Ellen Dixon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $321,850
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10617814

## Citation

> US National Institutes of Health, RePORTER application 10617814, Molecular choreography of CaV1.2 channels in the aging myocardium (5R01AG063796-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10617814. Licensed CC0.

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