PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle

Reiken, Steven; Lacampagne, Alain; Zhou, Hua; Kherani, Aftab R.; Lehnart, Stephan E.; Ward, Chris W.; Huang, Fannie; Gaburjáková, Marta; Gaburjáková, Jana; Rosemblit, Nora; Warren, Michelle; He, Kunlun; Yi, Geng–Hua; Wang, Jie; Burkhoff, Daniel; Vassort, Guy; Marks, Andrew R.

doi:10.1083/jcb.200211012

Cited by 230 publications

(253 citation statements)

References 52 publications

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“…release channel function through serine phosphorylation. 41,42 The second mutation, p.Gly4935Ser, identified in an MHS first-degree relative of the proband who had a fatal MH crisis, maps to the centre of the last transmembrane segment (amino acids 4918-4948) within the pore-forming region of RyR1 38 and a mutation hot spot, HS3b, where disease-associated mutations occur at a rate of about one in every three amino acids. 13 Furthermore, the p.Gly4935Ser was recently reported to be associated with MH in a large Brazilian pedigree.…”

Section: Discussionmentioning

confidence: 99%

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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Purpose Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population. Methods In this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families. Results Eighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations. Conclusions The distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing. RésuméObjectif L'hyperthermie maligne (HM) est une maladie pharmacoge´ne´tique he´re´ditaire dominante autosomique qui se manifeste lors de l'exposition des personnes susceptibles a`des anesthe´siques haloge´ne´s ou à la succinylcholine. E´tant donne´que l'HM est principalement associe´e aux mutations au niveau du ge`ne des re´cepteurs de ryanodine de type 1 (RYR1), l'objectif de cette e´tude e´tait de de´terminer la distribution et la fre´quence des mutations RyR1 causant une HM chez la population canadienne susceptible a`l'HM (SHM). Méthode Dans cette e´tude, nous avons examine´une cohorte repre´sentative de 36 personnes canadiennes SHM This article is accompanied by an editorial. Please see Can J Anesth 2011; 58: 6.

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Section: Discussionmentioning

confidence: 99%

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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“…They also suggest that hyperphosphorylation causes FKBPs to dissociate from RyRs, producing "leaky channels" (i.e., channels prone to open at rest). Such leaky channels could underlie increased risk for arrhythmias in heart failure and contribute to decreased muscle force production by reducing SR Ca 2þ store content (Marx et al 2000;Reiken et al 2003). However, other groups have not found PKA-dependent hyperphosphorylation in failing hearts (Xiao et al 2005).…”

Section: Pka and Camkii Phosphorylationmentioning

confidence: 99%

“…SNS activation causes b-adrenergic stimulation of the muscle, which via an intracellular signaling cascade results in activation of PKA. SNS-activated PKA phosphorylates RyR, altering its gating properties, but also phosphorylates several other key proteins involved in Ca 2þ handling such as troponin I and phospholamban (Valdivia et al 1995;Li et al 2000;Kentish et al 2001;Reiken et al 2003). Modified RyR function is associated with increased SR Ca 2þ leak in heart, which could contribute to reduced contractile function and increased propensity to arrhythmias.…”

Section: Pka and Camkii Phosphorylationmentioning

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

677

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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“…This charge neutralization, in turn, is thought to result in a conformational change in the protein. A common approach employed to investigate the functional effects of phosphorylation is to construct phosphomimetic mutations whereby glutamic or aspartic acid residues are substituted at the phosphoacceptor site (31,32). The rationale for this strategy is that the negatively charged side chain of the substituted acidic amino acid will mimic, to an extent, the addition of a phosphate moiety to the protein.…”

Section: Phosphomimetic Mutations In Functionally Important Phosphorymentioning

confidence: 99%

Functional Consequences of Phosphomimetic Mutations at Key cAMP-dependent Protein Kinase Phosphorylation Sites in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

Wagner

Joseph

et al. 2004

Journal of Biological Chemistry

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Regulation of Ca 2؉ release through inositol 1,4,5-trisphosphate receptors (InsP 3 R) has important consequences for defining the particular spatio-temporal properties of intracellular Ca 2؉ signals. In this study, regulation of Ca 2؉ release by phosphorylation of type 1 InsP 3 R (InsP 3 R-1) was investigated by constructing "phosphomimetic" charge mutations in the functionally important phosphorylation sites of both the S2؉ and S2؊ InsP 3 R-1 splice variants. Ca 2؉ release was investigated following expression in Dt-40 3ko cells devoid of endogenous InsP 3 R. In cells expressing either the S1755E S2؉ or S1589E/S1755E S2؊ InsP 3 R-1, InsP 3 -induced Ca 2؉ release was markedly enhanced compared with nonphosphorylatable S2؉ S1755A and S2؊ S1589A/ S1755A mutants. Ca 2؉ release through the S2؊ S1589E/ S1755E InsP 3 R-1 was enhanced ϳ8-fold over wild type and ϳ50-fold when compared with the nonphosphorylatable S2؊ S1589A/S1755A mutant. In cells expressing S2؊ InsP 3 R-1 with single mutations in either S1589E or S1755E, the sensitivity of Ca 2؉ release was enhanced ϳ3-fold; sensitivity was midway between the wild type and the double glutamate mutation. Paradoxically, forskolin treatment of cells expressing either single Ser/ Glu mutation failed to further enhance Ca 2؉ release. The sensitivity of Ca 2؉ release in cells expressing S2؉ S1755E InsP 3 R-1 was comparable with the sensitivity of S2؊ S1589E/S1755E InsP 3 R-1. In contrast, mutation of S2؉ S1589E InsP 3 R-1 resulted in a receptor with comparable sensitivity to wild type cells. Expression of S2؊ S1589E/S1755E InsP 3 R-1 resulted in robust Ca 2؉ oscillations when cells were stimulated with concentrations of ␣-IgM antibody that were threshold for stimulation in S2؊ wild type InsP 3 R-1-expressing cells. However, at higher concentrations of ␣-IgM antibody, Ca 2؉ oscillations of a similar period and magnitude were initiated in cells expressing either wild type or S2؊ phosphomimetic mutations. Thus, regulation by phosphorylation of the functional sensitivity of InsP 3 R-1 appears to define the threshold at which oscillations are initiated but not the frequency or amplitude of the signal when established.Inositol 1,4,5-trisphosphate receptors are intracellular ion channels that function to couple the activation of cell surface receptors for neurotransmitters, hormones, and growth factors to the initiation of intracellular Ca 2ϩ release (1). Three genes have been cloned that encode distinct proteins of a molecular mass of ϳ300 kDa, named the type 1 (InsP 3 R-1), 1 type 2 (InsP 3 R-2), and type 3 (InsP 3 R-3) InsP 3 Rs (2-4). In addition, multiple receptor proteins with distinct tissue distributions are produced by alternate splicing of the type 1 receptor gene (5, 6). Most cells express multiple isoforms of InsP 3 R (7). Furthermore, the expression level and complement of receptors differ in individual tissues, and this together with regulation of the activity of the channel is thought to be a major determinant of the rich diversity of Ca 2ϩ signaling events observed ...

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PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle

Cited by 230 publications

References 52 publications

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

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

Functional Consequences of Phosphomimetic Mutations at Key cAMP-dependent Protein Kinase Phosphorylation Sites in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

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