# L-type channel trafficking and modulation in heart

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $714,900

## Abstract

SUMMARY
 The cardiac L-type Ca2+ channel plays a key role in cardiac excitation-contraction coupling, action potential
duration, and gene expression. Abnormalities in CaV1.2 function, including increased long-opening-mode
gating and blunted adrenergic responsiveness, are associated with heart failure and hypertrophy. The
increased activation of CaV1.2, in turn, triggers Ca2+-responsive signaling pathways, which contribute to the
pathogenesis of heart failure and hypertrophy. Proper targeting of CaV1.2 to distinct surface sites, and
hormonal regulation of their activity, is vital for normal cardiac physiology. Cav1.2 in heart is associated with
large supramolecular complexes that impact on channel trafficking, localization, turnover, and function. Much
of the prevailing dogma relating to mechanisms underlying CaV1.2 trafficking and modulation is derived from
studies using recombinant channels reconstituted in heterologous expression systems. Unfortunately,
however, at least some of the most critical questions regarding trafficking and regulation by -adrenergic
agonists in cardiomyocytes cannot be assessed using heterologous expression, likely because the unique
intracellular environment of cardiomyocytes is not reproduced elsewhere. In the previous funding period, we
developed and implemented innovative methods to probe determinants underlying CaV1.2 trafficking and β-
adrenergic regulation directly in cardiomyocytes. Using this approach, our findings that β-less α1C in adult
cardiomyocytes generate CaV1.2 channels with normal basal activity that are not regulated by PKA provide the
first opportunity to probe the relative contribution of this modulation to sympathetic regulation in the fight or
flight response. We propose three Aims that build on our previous findings, and designed to deepen
mechanistic understanding of CaV1.2 regulation in heart: (1) Determine the role of CaV binding to 1C in
regulating cardiac contractility in vivo; (2) To determine the mechanism(s) by which  subunits enable -
adrenergic regulation of CaV1.2. (3) To elucidate the mechanisms of β-dependent and β-independent CaV1.2
channel trafficking. The three Aims, which should provide key new understandings concerning the regulation of
Ca2+ influx in cardiomyocytes, are highly relevant towards understanding cardiac pathologies and the
molecular mechanisms responsible for cardiac excitation-contraction coupling and adrenergic modulation of
the cardiac Ca2+ channel.

## Key facts

- **NIH application ID:** 10147136
- **Project number:** 5R01HL121253-08
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Henry M. Colecraft
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $714,900
- **Award type:** 5
- **Project period:** 2014-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147136

## Citation

> US National Institutes of Health, RePORTER application 10147136, L-type channel trafficking and modulation in heart (5R01HL121253-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147136. Licensed CC0.

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