# RyR architecture and gatekeeping of internal calcium stores

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $378,925

## Abstract

PROJECT SUMMARY
 The intracellular, large conductance intracellular RyR calcium release channel is a major
regulator of calcium homeostasis in skeletal and cardiac muscle cells. Naturally occurring mutations
in the skeletal isoform RyR1 lead to several myopathies (central core disease, multi-minicore disease,
nemaline myopathy, exertional rhabdomyolysis) and malignant hyperthermia, whereas mutations in
the cardiac isoform RyR2 lead to arrhythmia and heart failure. Some post-translational modifications
can also cause similar effects in wild type RyR1 and RyR2. The vast majority of these RyR alterations
cause disruption of calcium homeostasis through RyR hypersensitization, which causes sub-
threshold opening and sarcoplasmic reticulum calcium leak.
 The project applies state-of-the-art structural biology technology to determine RyR's structure and
allosterism at the atomic level and in a near-native state, in order to examine the molecular
mechanism of RyR-mediated calcium leak and analyze how similar modifications affect differently the
two RyR isoforms. We will determine the atomic structure of selected RyR1 and RyR2 mutants, and
wt RyR1 or RyR2 with post-translational modifications, using cryoEM and 3D image reconstruction.
Reaching atomic resolution of non-crystalline samples by cryoEM is now possible owing to the recent
development of direct electron detectors for electron microscopy. To further establish and
characterize possible heterogeneity in the dataset, classification and multivariate statistical analysis of
several thousand RyR cryoEM particles will be performed. Mutant RyRs will be purified from HEK cell
lines, and post-translational modifications will be studied on RyR purified from rabbit.
 Solving the atomic structure of RyR with disease-related alterations will help to understand the
molecular mechanism of defective channel closure, and reveal any differential mechanisms between
the skeletal and cardiac isoforms. This will advance the field forward towards structure-based,
isoform-specific drug design.

## Key facts

- **NIH application ID:** 10252844
- **Project number:** 5R01AR068431-05
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Montserrat Samso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,925
- **Award type:** 5
- **Project period:** 2017-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10252844

## Citation

> US National Institutes of Health, RePORTER application 10252844, RyR architecture and gatekeeping of internal calcium stores (5R01AR068431-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10252844. Licensed CC0.

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