Agonists and antagonists of the cardiac Ryanodine receptor:potential therapeutic agents?

Angela F Dulhunty, Nicole A Beard, Pierre Pouliquin, Marco G Casarotto

Research output: Contribution to journalReview article

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)247-263
Number of pages17
JournalPharmacology and Therapeutics
Volume113
Issue number2
DOIs
Publication statusPublished - Feb 2007
Externally publishedYes

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Ryanodine Receptor Calcium Release Channel
Therapeutics
Heart Diseases
Tacrolimus
Cardiac Arrhythmias
Heart Failure
Protective Agents
Proteins
Drug Design
Immunosuppressive Agents
Pharmaceutical Preparations
Myocardial Ischemia
Carrier Proteins
Binding Sites
Morbidity

Cite this

Dulhunty, Angela F ; Beard, Nicole A ; Pouliquin, Pierre ; Casarotto, Marco G. / Agonists and antagonists of the cardiac Ryanodine receptor:potential therapeutic agents?. In: Pharmacology and Therapeutics. 2007 ; Vol. 113, No. 2. pp. 247-263.
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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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Agonists and antagonists of the cardiac Ryanodine receptor:potential therapeutic agents? / Dulhunty, Angela F; Beard, Nicole A; Pouliquin, Pierre; Casarotto, Marco G.

In: Pharmacology and Therapeutics, Vol. 113, No. 2, 02.2007, p. 247-263.

Research output: Contribution to journalReview article

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T1 - Agonists and antagonists of the cardiac Ryanodine receptor:potential therapeutic agents?

AU - Dulhunty, Angela F

AU - Beard, Nicole A

AU - Pouliquin, Pierre

AU - Casarotto, Marco G

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N2 - 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.

AB - 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.

KW - Animals

KW - Calcium Signaling

KW - Heart Diseases

KW - Humans

KW - Ryanodine Receptor Calcium Release Channel

KW - Sarcoplasmic Reticulum

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DO - 10.1016/j.pharmthera.2006.08.007

M3 - Review article

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JO - Pharmacology Therapeutics

JF - Pharmacology Therapeutics

SN - 0163-7258

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ER -