# Coupled Gating of L-type Calcium Channels in Heart

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $454,743

## Abstract

Project Summary
The work outlined in this application stems from our recent discovery that dihydropyridine-sensitive, voltage-
gated CaV1.2 and CaV1.3 channels form clusters that undergo dynamic allosteric interactions, which allow
cooperative gating of these channels in cardiac myocytes. The significance of these findings is underscored
by our demonstration that coupled activation of these channels modulates pace-making activity in sinoatrial
node (SAN) cells (CaV1.2 and CaV1.3) and contraction in ventricular myocytes (CaV1.2) under physiological
and pathological conditions. The experiments proposed in this application test a novel model for the regulation
of CaV1.2 and CaV1.3 channel activity in SAN and ventricular myocytes. In this model, CaV1.2 and CaV1.3
channels undergo reciprocal physical and functional interactions that are initiated by increases in intracellular
Ca2+ concentration ([Ca2+]i). During the action potential, channel-to-channel coupling is initiated when
membrane depolarization opens CaV1.2 and CaV1.3 channels, allowing a small amount of Ca2+ to enter the
cell. The incoming Ca2+ binds to calmodulin (CaM), thereby promoting physical coupling of adjacent channels
via the pre-IQ domains located in the C-tails of the channels. Physical contact increases the activity of adjoined
channels. As individual channels within a cluster inactivate and close, [Ca2+]i decreases and coupling fades,
but persists longer than the current that evoked it, serving as a type of `molecular memory'. A new concept in
our model is that the overall activity of CaV1.2 and CaV1.3 channels within a cluster depends on the number of
channels that couple and the duration of these interactions. The project will test the physiological and
pathological implications of this model in three specific aims. Specific aim 1 tests the hypothesis that coupling
between CaV1.2 and CaV1.3 channels in SAN cells regulates pace-making activity. Specific aim 2 tests the
hypothesis that persistent CaV1.2 channel coupling in ventricular myocytes induces long-term potentiation of
Ca2+ currents and increases contractility. Specific aim 3 tests the hypothesis that long-QT syndrome CaM
mutants increase the probability of arrhythmogenesis by altering functional coupling between CaV1.2 channels.
Diverse, state-of-the-art methods, including patch-clamp electrophysiology, optical clamping, optogenetics and
confocal, TIRF, and super-resolution microscopy, will be used to achieve these aims.

## Key facts

- **NIH application ID:** 9838766
- **Project number:** 5R01HL085686-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Luis F Santana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,743
- **Award type:** 5
- **Project period:** 2007-04-20 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838766

## Citation

> US National Institutes of Health, RePORTER application 9838766, Coupled Gating of L-type Calcium Channels in Heart (5R01HL085686-14). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9838766. Licensed CC0.

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