What we don't know about the structure of ryanodine receptor calcium release channels

Dulhunty, Angela F.; Pouliquin, Pierre

doi:10.1046/j.1440-1681.2003.03904.x

Cited by 44 publications

(29 citation statements)

References 111 publications

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“…Novel mutations localized along the transcript could certainly affect the function of RYR1, taking into account the fact that the RYR1 gene contains several ligand binding sites as well as conserved domains according to the SwissPfam protein database and previously reported findings [Dulhunty and Pouliquin, 2003]. The N-terminal region (216-572) has been reported to have a similar structure as the IP3R core region and to be involved in the regulation of Ca 21 channel activity [Serysheva et al, 2005].…”

Section: Characterization Of Novel Ryr1 Mutationsmentioning

confidence: 97%

Increasing the number of diagnostic mutations in malignant hyperthermia

et al. 2009

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Malignant hyperthermia (MH) is an autosomal dominant disorder characterized by abnormal calcium homeostasis in skeletal muscle in response to triggering agents. Today, genetic investigations on ryanodine receptor type 1 (RYR1) gene and alpha1 subunit of the dihydropyridine receptor (DHPR) (CACNA1S) gene have improved the procedures associated with MH diagnosis. In approximately 50% of MH cases a causative RYR1 mutation was found. Molecular genetic testing based on RYR1 mutations for MH diagnosis is challenging, because the causative mutations, most of which are private, are distributed throughout the RYR1 gene. A more comprehensive genetic testing procedure is needed. Therefore, we aim to expand the genetic information related to MH and to evaluate the effect of mutations on the MH phenotype. Performing an in-depth mutation screening of the RYR1 transcript sequence in 36 unrelated MH susceptible (MHS) patients, we identified 17 novel, five rare, and eight non-disease-causing variants in 23 patients. The 13 remaining MHS patients presented no known variants, neither in RYR1 nor in the CACNA1S binding regions to RYR1. The 17 novel variants were found to affect highly conserved amino acids and were absent in 100 controls. Excellent genotype-phenotype correlations were found by investigating 21 MHS families-a total of 186 individuals. Epstein-Barr virus (EBV) lymphoblastoid cells carrying four of these novel mutations showed abnormal calcium homeostasis. The results of this study contribute to the establishment of a robust genetic testing procedure for MH diagnosis.

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Section: Characterization Of Novel Ryr1 Mutationsmentioning

confidence: 97%

Increasing the number of diagnostic mutations in malignant hyperthermia

et al. 2009

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“…The position of the final pair of TMD and the role of the intervening loop in forming a selectivity filter are clear (see Fig. 1A) (13,19,24). This region is most conserved within RyR and IP 3 R (see Fig.…”

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confidence: 96%

“…The transmembrane topology of RyR is more contentious (18,19). It is clear that the N and C termini are cytosolic (20), that the only TMD lie toward the C terminus, and that all models share four TMD, but there have been competing claims for [4][5][6][7][8][9][10][11][12].…”

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confidence: 99%

Targeting and Retention of Type 1 Ryanodine Receptors to the Endoplasmic Reticulum

Meur

Parker

Gergely³

et al. 2007

Journal of Biological Chemistry

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Most ryanodine receptors and their relatives, inositol 1,4,5-trisphosphate receptors, are expressed in the sarcoplasmic or endoplasmic reticulum (ER), where they mediate Ca 2؉ release. We expressed fragments of ryanodine receptor type 1 (RyR1) in COS cells alone or fused to intercellular adhesion molecule-1 (ICAM-1), each tagged with yellow fluorescent protein, and used confocal imaging and glycoprotein analysis to identify the determinants of ER targeting and retention. Single transmembrane domains (TMD) of RyR1 taken from the first (TMD1-TMD2) or last (TMD5-TMD6) pair were expressed in the ER membrane. TMD3-TMD4 was expressed in the outer mitochondrial membrane. The TMD outer pairs (TMD1-TMD2 and TMD5-TMD6) retained ICAM-1, a plasma membrane-targeted protein, within the ER membrane. TMD1 alone provided a strong ER retention signal and TMD6 a weaker signal, but the other single TMD were unable to retain ICAM-1 in the ER. We conclude that TMD1 provides the first and sufficient signal for ER targeting of RyR1. The TMD outer pairs include redundant ER retention signals, with TMD1 providing the strongest signal.Ryanodine receptors (RyR) 3 compose a family of intracellular Ca 2ϩ channels that mediate release of Ca 2ϩ from the intracellular stores of excitable and non-excitable cells (1). The three mammalian subtypes of RyR (types 1-3) share ϳ70% amino acid sequence identity, and they are also related to inositol 1,4,5-trisphosphate receptors (IP 3 R) (1, 2). All subtypes of each of the major families of intracellular Ca 2ϩ channels are expressed predominantly, although not exclusively, in the endoplasmic reticulum (ER) or sarcoplasmic reticulum (3, 4). Both families of channels are regulated by diverse intracellular signals, and they also share structural features. All IP 3 R are co-regulated by Ca 2ϩ and inositol 1,4,5-trisphosphate (5), and they are modulated by many additional signals (6). RyR are also regulated by cytosolic Ca 2ϩ and modulated by many of the signals that regulate IP 3 R (1), but RyR subtypes differ in their most important modes of physiological regulation. RyR1, the major isoform of skeletal muscle, is activated by depolarization of the sarcolemma transmitted from dihydropyridine receptors in the plasma membrane to RyR in the junctional sarcoplasmic reticulum (7). In cardiac muscle, the major activator of RyR2 is the local increase in cytosolic [Ca 2ϩ ] that follows depolarizationevoked activation of dihydropyridine receptors. In other cells in which each of the three RyR subtypes can be expressed (8), cytosolic Ca 2ϩ and such signals as cyclic ADP-ribose (9) are probably the major regulators of RyR.Both IP 3 R and RyR form homo-or heterotetrameric assemblies of subunits (3, 10). Each subunit contains a large cytosolic N-terminal domain, a short C-terminal tail, and a stretch of hydrophobic transmembrane domains (TMD), the last two of which form a cation-selective pore with the intervening luminal loop (11-13). The biophysical properties and probably the structure of the pore are similar for...

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“…The pore sequences are largely found in membrane spanning domains. 2 There is a large cytosolic domain. Although hyperphosphorylation refers, by definition, to the occupation of all the putative phosphorylation sites in a molecule in the context of the work by Marks and colleagues, 1 hyperphosphorylation refers to 3 or perhaps 4 of the serine residues.…”

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confidence: 99%