# Mechanisms of couplon-linked skeletal muscle myopathies

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $651,624

## Abstract

The skeletal muscle L-type Ca2+ channel (CaV1.1) in the transverse tubules, the ryanodine receptor (RyR1) in the
sarcoplasmic reticulum (SR), and calsequestrin (Casq1) in the lumen of junctional SR (jSR) are key components of
a macromolecular complex termed the couplon which regulates excitation-contraction coupling (ECC). Mutations in
RyR1, CaV1.1, and Casq1 underlie human myopathies with overlapping pathological features. With the exception of
dantrolene for malignant hyperthermia, there are no FDA approved interventions for any of these myopathies. Mice
with a mutations CaV1.1 (E1014K), RyR1 (I4895T) and Casq1 (D244G) develop myopathies that increase in severity
with age and their muscles display Casq1 mislocalization and persistent ER stress. This application is designed to
elucidate the mechanisms by which mutation-associated alterations in a CaMKII-dependent pathway lead to ER
stress/UPR and muscle disease. We will test the general hypothesis that the similarities in couplon myopathies
arising from mutations in different couplon proteins are due to highly cooperative, bidirectional functional coupling
between CaV1.1, CaMKII, RyR1 and Casq1. Our aims are to: 1. Define the roles of altered CaV1.1 functional state
transitions and CaMKII activation in couplon myopathies. 2. Quantify the effects of couplon disease-associated
mutations on RyR1 phosphorylation and the phosphorylation-mediated effects on CaV1.1 function and Casq1
retention at the jSR. 3. Define the roles of Casq1 mislocalization and ER stress in the couplon myopathies. We will
also test the ability of 4PBA, which alleviates ER stress, to improve muscle function in myopathies that arise from
mutations in couplon proteins.

## Key facts

- **NIH application ID:** 10198771
- **Project number:** 5R01AR072602-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** SUSAN L HAMILTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $651,624
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198771

## Citation

> US National Institutes of Health, RePORTER application 10198771, Mechanisms of couplon-linked skeletal muscle myopathies (5R01AR072602-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10198771. Licensed CC0.

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