Molecular Basis of Calmodulin Binding to Cardiac Muscle Ca2+ Release Channel (Ryanodine Receptor)

Yamaguchi, Naohiro; Xu, Le; Pasek, Daniel A.; Evans, Kelly E.; Meissner, Gerhard

doi:10.1074/jbc.m301125200

Cited by 145 publications

(198 citation statements)

References 23 publications

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“…Amino acids 3615 -3628 contact the carboxy lobe of CaM, whereas amino acids 3628 -3637 bind the amino lobe of CaM. In cardiac muscle, CaM shifts the Ca 2þ -dependence of RyR2 activation to higher Ca 2þ concentrations and hence decreases the RyR2 opening at all Ca 2þ concentrations (Balshaw et al 2001;Yamaguchi et al 2003). Recently reduced affinity for CaM binding to RyR2 with PKA phosphorylation was found in a CPVT-associated mouse model (Arg2474Ser), resulting in spontaneous local Ca 2þ release events leading to lethal arrythmias (Xu et al 2010).…”

Section: Calmodulinmentioning

confidence: 99%

“…ApoCaM is a partial agonist whereas CaCaM is an inhibitor of RyR1 and SR Ca 2þ release (Rodney et al 2000). CaM binding site involves amino acids 3614 -3643 of the RyR1 rabbit sequence (Takeshima et al 1989;Moore et al 1999b;Yamaguchi et al 2003;Zhang et al 2003). Cryo-EM difference mapping of the three-dimensional structures of RyR1 with and without added CaM has suggested that the CaCaM binding site is located in subdomain 3.…”

Section: Calmodulinmentioning

confidence: 99%

See 1 more Smart Citation

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

658

572

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Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

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Section: Calmodulinmentioning

confidence: 99%

Section: Calmodulinmentioning

confidence: 99%

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

658

572

View full text Add to dashboard Cite

show abstract

“…Recently, mutations in CaM have also been shown to cause CPVT 31, 32, 33. Considering CaM binding to the cytosolic surface of RyR2 has been reported to contribute to inactivation of RyR2,17, 18, 19, 20 we tested whether arrhythmogenic mutations of CaM also act by shortening RyR2 refractoriness. Ca imaging was performed in permeabilized cardiac myocytes (cytosolic Ca buffered at 120 nmol/L) supplemented with different CaM protein variants 34, 35.…”

Section: Resultsmentioning

confidence: 99%

“…In cardiac cells, most CaM is bound to RyR2 and inhibits its activity in a Ca‐dependent manner 17, 18, 19, 20. Such Ca dependent binding would be expected to inhibit RyR2 specifically after Ca release lasting late into the diastolic period.…”

mentioning

confidence: 99%

Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Liu

Walton

et al. 2018

JAHA

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BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral‐mediated delivery to alleviate arrhythmias in non–CaM‐related CPVT.Methods and ResultsTo that end, we have designed a CaM protein (GSH‐M37Q; dubbed as therapeutic CaM or T‐CaM) that exhibited a slowed N‐terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from CPVT mice carrying the CASQ2 mutation R33Q. This T‐CaM was introduced to the heart of R33Q mice through recombinant adeno‐associated viral vector serotype 9. Eight weeks postinfection, we performed confocal microscopy to assess Ca handling and recorded surface ECGs to assess susceptibility to arrhythmias in vivo. During catecholamine stimulation with isoproterenol, T‐CaM reduced isoproterenol‐promoted diastolic Ca waves in isolated CPVT cardiomyocytes. Importantly, T‐CaM exposure abolished ventricular tachycardia in CPVT mice challenged with catecholamines.ConclusionsOur results suggest that gene transfer of T‐CaM by adeno‐associated viral vector serotype 9 improves myocyte Ca handling and alleviates arrhythmias in a calsequestrin‐associated CPVT model, thus supporting the potential of a CaM‐based antiarrhythmic approach as a therapeutic avenue for genetically distinct forms of CPVT.

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“…In addition to the three mammalian isoforms described below, various nonmammalian isoforms of the ryanodine receptor have been identified and these are discussed in Sutko and Airey (1996). The function of the ryanodine receptor channels may also be influenced by closely associated proteins such as the tacrolimus (FK506)-binding protein, calmodulin (Yamaguchi et al, 2003) The modulators of channel function included in this table are those most commonly used to identify ryanodine-sensitive Ca 2+ release pathways. Numerous other modulators of ryanodine receptor/channel function can be found in the reviews listed below.…”

Section: Ryanodine Receptormentioning

confidence: 99%

Ligand-gated Ion Channels

Encyclopedic Reference of Molecular Pharmacology

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Molecular Basis of Calmodulin Binding to Cardiac Muscle Ca2+ Release Channel (Ryanodine Receptor)

Cited by 145 publications

References 23 publications

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Ligand-gated Ion Channels

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