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Updated: Jul 19, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Agonists and antagonists of the cardiac ryanodine receptor: potential therapeutic agents?
Angela F Dulhunty1, Nicole A Beard, Pierre Pouliquin
1Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, P.O. Box 334, ACT, 2601, Australia.
Insights
The intracellular ryanodine receptor (RyR) Ca2+ channel is a promising therapeutic target for heart disease. Modulating RyR activity offers potential treatments for conditions like heart failure and arrhythmias.
Area of Science:
- Cardiovascular Research
- Molecular Pharmacology
- Medical Genetics
Background:
- Heart disease, including ischemic heart disease and heart failure, presents significant mortality and morbidity.
- Genetic defects and drug-induced modifications of the intracellular ryanodine receptor (RyR) Ca2+ release channel are implicated in various heart conditions.
- Dysfunctional Ca2+ signaling, linked to RyR, varies with heart disease type and progression, necessitating tailored therapeutic strategies.
Purpose of the Study:
- To review the potential of the intracellular ryanodine receptor (RyR) Ca2+ release channel as a therapeutic target in heart disease.
- To explore how modulating RyR activity can address specific Ca2+ signaling defects in different cardiac conditions.
- To discuss the development of novel RyR-based therapeutic agents, including those targeting RyR-associated proteins.
Main Methods:
- Review of existing literature on RyR function and its role in heart disease.
- Analysis of Ca2+ signaling pathways and their modulation by RyR.
- Discussion of drug discovery approaches targeting RyR and its regulatory proteins, including FKBP12.6.
Main Results:
- The RyR Ca2+ channel is a credible therapeutic target for heart disease.
- Compounds activating RyR may serve as inotropic agents, enhancing cardiac contraction.
- Compounds inhibiting RyR activity could treat arrhythmias and Ca2+ depletion in heart failure.
Conclusions:
- Targeting the RyR offers a promising avenue for novel heart disease therapies.
- Stabilizing RyR interactions, as with JTV519 and FKBP12.6, validates RyR as a drug target.
- Investigating RyR-linked arrhythmias may lead to the discovery of new therapeutic agents.
Abstract:
This review addresses the potential use of the intracellular ryanodine receptor (RyR) Ca(2+) release channel as a therapeutic target in heart disease. Heart disease encompasses a wide range of conditions with the major contributors to mortality and morbidity being ischaemic heart disease and heart failure (HF). In addition there are many rare, but devastating conditions, some of which are either genetically linked to the RyR and its regulatory proteins or involve drug-induced modification of the proteins. The defects in Ca(2+) signalling vary with the nature of the heart disease and the stage in its progress and therefore specific corrections require different modifications of Ca(2+) signalling. Compounds that activate the RyR are potential inotropic agents to increase the Ca(2+) transient and strength of contraction. Compounds that reduce RyR activity are potentially useful in conditions where excess RyR activity initiates arrhythmias, or depletes the Ca(2+) store, as in end stage HF. It has recently been discovered that the cardio-protective action of the drug JTV519 can be attributed partly to its ability to stabilise the interaction between the RyR and the 12.6 kDa binding protein for the commonly used immunosuppressive drug FK506 (FKBP12.6, known as tacrolimus). This has established the credibility of the RyR as a therapeutic target. We explore the possibility that mutations causing the rare RyR-linked arrhythmias will open the door to identification of novel RyR-based therapeutic agents. The use of regulatory binding sites within the RyR complex or on its associated proteins as templates for drug design is discussed.
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