# The Molecular Transitions that Initiate EC Coupling in Skeletal Muscle

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $390,005

## Abstract

PROJECT SUMMARY/ABSTRACT
The motivation for these studies is the need to gain an understanding of the fundamental biophysical
properties of the skeletal voltage-gated L-type Calcium channel CaV1.1. While ion conduction is a
critical feature (and often the only duty) of the vast majority of ion channels, CaV1.1 is somewhat
unique: the activation of its voltage sensors opens its pore, but Ca2+ entry is not required to trigger
muscle contraction. Instead, the conformational changes of Cav1.1 voltage sensors directly gate
Ryanodine receptors (RyR1) via a physical coupling between these two channels, to trigger the release
of sarcoplasmic reticulum Ca2+. In this context, the four voltage-sensing elements of Cav1.1 are indeed
the voltage sensors of RyR1 channels. As the possibility to express Cav1.1 channel in oocytes has
recently become feasible thanks to the discovery of an essential adaptor protein (Stac3), the Olcese
laboratory is in a privileged position to directly address the mechanism of voltage regulation in this
protein, with a unique capability (to date) to implement the cutting-edge voltage clamp fluorometry
approach to CaV channels.
During the next five years, using electrophysiological, optical and computational techniques, the
investigators will delineate the basis of voltage dependence in CaV1.1 channels, in both adult and
embryonic splice variants. They will interrogate how this voltage dependence is modulated by the
participation of auxiliary subunits (β, α2δ, and γ) in the CaV1.1 macromolecular complex. They will
determine which of the four homologous, but non-identical CaV1.1 Voltage Sensing Domains confer
voltage sensitivity to RyR1-mediated Ca release. Finally, the investigators will address the molecular
mechanism of a malignant-hyperthermia-causing mutation that specifically affects the voltage-sensing
apparatus of CaV1.1. The knowledge gathered by is critical to understand fundamental aspects of
muscle physiology and the voltage-dependent control of contraction.

## Key facts

- **NIH application ID:** 10371036
- **Project number:** 5R35GM131896-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Riccardo Olcese
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,005
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371036

## Citation

> US National Institutes of Health, RePORTER application 10371036, The Molecular Transitions that Initiate EC Coupling in Skeletal Muscle (5R35GM131896-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371036. Licensed CC0.

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