Related Experiment Video
Updated: Aug 6, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies
A F Dulhunty1, N A Beard, P Pouliquin
1Division of Molecular Bioscience, JCSMR and RSC, ANU, Canberra, ACT, 2601, Australia. angela.dulhunty@anu.edu.au
Abstract:
There are many mutations in the ryanodine receptor (RyR) Ca2+ release channel that are implicated in skeletal muscle disorders and cardiac arrhythmias. More than 80 mutations in the skeletal RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in the cardiac RyR2 lead to ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling in the muscle fibres. In a different myopathy, myotonic dystrophy (DM), a juvenile isoform of the skeletal RyR is preferentially expressed in adults. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). The juvenile isoform (ASI(-)) is less active than the adult isoform (ASI(+)) and its over-expression in adults with DM may contribute to functional changes. Finally, mutations in an important regulator of the RyR, the Ca2+ binding protein calsequestrin (CSQ), have been linked to a disruption of Ca2+ homeostasis in cardiac myocytes that results in arrhythmias. We discuss evidence supporting the hypothesis that mutations in each of these situations alter protein/protein interactions within the RyR complex or between the RyR and its associated proteins. The disruption of these protein-protein interactions can lead either to excess Ca2+ release or reduced Ca2+ release and thus to abnormal Ca2+ homeostasis. Much of the evidence for disruption of protein-protein interactions has been provided by the actions of a group of novel RyR regulators, domain peptides with sequences that correspond to sequences within the RyR and which compete with the endogenous residues for their interaction sites.
Insights
Mutations in the ryanodine receptor (RyR) and its regulators disrupt calcium signaling, causing muscle disorders and cardiac arrhythmias by altering protein interactions. Novel RyR regulators help elucidate these mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiology
Background:
- Mutations in ryanodine receptor (RyR) Ca2+ channels are linked to skeletal muscle disorders and cardiac arrhythmias.
- Over 80 RyR1 mutations cause conditions like malignant hyperthermia, while over 40 RyR2 mutations lead to sudden cardiac death.
- RyR dysfunction disrupts Ca2+ signaling, and altered expression of RyR isoforms, like in myotonic dystrophy, contributes to myopathies.
Purpose of the Study:
- To explore the hypothesis that mutations in RyR, its regulators (like calsequestrin), or altered isoform expression disrupt protein-protein interactions.
- To understand how these disrupted interactions lead to abnormal Ca2+ homeostasis and associated diseases.
- To highlight the role of novel RyR regulators in studying these protein-protein interactions.
Main Methods:
- Review of existing literature on RyR mutations and their clinical implications.
- Analysis of studies investigating altered RyR isoform expression in myotonic dystrophy.
- Examination of research on calsequestrin mutations and their effect on cardiac Ca2+ homeostasis.
- Investigation of the mechanism of action of domain peptides as RyR regulators.
Main Results:
- RyR mutations cause diverse changes in channel activity, leading to either excessive Ca2+ release or channel blockade.
- In myotonic dystrophy, preferential expression of a less active juvenile RyR isoform (ASI(-)) in adults may cause functional deficits.
- Mutations in calsequestrin (CSQ) disrupt cardiac Ca2+ homeostasis, resulting in arrhythmias.
- Domain peptides, mimicking RyR sequences, compete with endogenous interactions, providing evidence for disrupted protein-protein binding.
Conclusions:
- Mutations in RyR, its regulators, or altered isoform expression disrupt critical protein-protein interactions within the RyR complex.
- These disruptions lead to abnormal Ca2+ homeostasis, manifesting as skeletal muscle disorders or cardiac arrhythmias.
- Novel RyR regulators, such as domain peptides, are valuable tools for dissecting these complex molecular interactions and their pathological consequences.
More Related Videos
12:43Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study
Published on: July 27, 2016
09:36Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
Published on: December 22, 2023
