Neuronal Ryanodine Receptors in Development and Aging

Abu-Omar, Nawaf; Das, Jogita; Szeto, Vivian; Feng, Zhong‐Ping

doi:10.1007/s12035-016-0375-4

Cited by 63 publications

(47 citation statements)

References 100 publications

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“…RYR family has 3 different ryanodine receptor genes, RYR1 , RYR2 and RYR3 , which conduct 3 isoforms of RyRs with 70% sequence homology. RyRs serve as a calcium release channel in the endoplasmic reticulum and are broadly expressed across all organs in different patterns, including the central nervous system . Many neuromuscular diseases are caused by mutations in RYR1 and RYR2 .…”

Section: Discussionmentioning

confidence: 99%

Novel West syndrome candidate genes in a Chinese cohort

Peng

Wang

et al. 2018

CNS Neurosci Ther

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Section: Discussionmentioning

confidence: 99%

Novel West syndrome candidate genes in a Chinese cohort

Peng

Wang

et al. 2018

CNS Neurosci Ther

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show abstract

“…The cerebral expression of RyRs is under tight regulation undergoing changes throughout development from embryonic to adult. Altered calcium signaling and RyR dysregulation have been implicated in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease (Abu-Omar, Das, Szeto, & Feng, 2017). TRHDE, KCNC2, and ATXN7L3B are genes located closest to the chromosome 12 breakpoint.…”

Section: Haplotype Analysismentioning

confidence: 99%

Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes

Luukkonen

Mehrjouy

Pöyhönen

et al. 2017

Molec Gen & Gen Med

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BackgroundThe risk of serious congenital anomaly for de novo balanced translocations is estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a “Systematic Survey of Balanced Chromosomal Rearrangements in Finns.” In the first family, carriers (n = 6) manifest with learning problems in childhood, and later with unexplained neurological symptoms (chronic headache, balance problems, tremor, fatigue) and cerebral infarctions in their 50s. In the second family, two carriers suffer from tetralogy of Fallot, one from transient ischemic attack and one from migraine. The translocation cosegregates with these vascular phenotypes and neurological symptoms.Methods and ResultsWe narrowed down the breakpoint regions using mate pair sequencing. We observed conserved haplotypes around the breakpoints, pointing out that this translocation has arisen only once. The chromosome 1 breakpoint truncates a CHRM3 processed transcript, and is flanked by the 5′ end of CHRM3 and the 3′ end of RYR2. TRHDE,KCNC2, and ATXN7L3B flank the chromosome 12 breakpoint.ConclusionsThis study demonstrates a balanced t(1;12)(q43;q21.1) with conserved haplotypes on the derived chromosomes. The translocation seems to result in vascular phenotype, with or without neurological symptoms, in at least two families. We suggest that the translocation influences the positional expression of CHRM3,RYR2,TRHDE,KCNC2, and/or ATXN7L3B.

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“…Upon stimulation by the adjacent dihydropyridine receptor (DHPR), RyR opens and releases large amounts of Ca 2+ down its gradient from the endo/sarcoplasmic reticulum into the cytosol, which triggers excitation-contraction coupling in muscle (Eisner et al 2017, Hernandez-Ochoa et al 2015. Activation of RyR also generates downstream effects in neurons (Abu-Omar et al 2018) and other cell types (Hosoi et al 2001, Lewarchik et al 2014. The three mammalian isoforms are RyR1, RyR2 and RyR3: skeletal muscle expresses RyR1, cardiac muscle expresses RyR2, and brain expresses all isoforms.…”

Section: Introductionmentioning

confidence: 99%

The FKBP12 subunit modifies the long-range allosterism of the ryanodine receptor

Steele

Samsó

2019

Journal of Structural Biology

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Ryanodine receptors (RyRs) are large conductance intracellular channels controlling intracellular calcium homeostasis in myocytes, neurons, and other cell types. Loss of RyR's constitutive cytoplasmic partner FKBP results in channel sensitization, dominant subconductance states, and increased cytoplasmic Ca 2+. FKBP12 binds to RyR1's cytoplasmic assembly 130 Å away from the ion gate at four equivalent sites in the RyR1 tetramer. To understand how FKBP12 binding alters RyR1's channel properties, we studied the 3D structure of RyR1 alone in the closed conformation in the context of the open and closed conformations of FKBP12-bound RyR1. We analyzed the metrics of conformational changes of existing structures, the structure of the ion gate, and carried out multivariate statistical analysis of thousands of individual cryoEM RyR1 particles. We find that under closed state conditions, in the presence of FKBP12, the cytoplasmic domain of RyR1 adopts an upward conformation, whereas absence of FKBP12 results in a relaxed conformation, while the ion gate remains closed. The relaxed conformation is intermediate between the RyR1-FKBP12 complex closed (upward) and open (downward) conformations. The closed-relaxed conformation of RyR1 appears to be consistent with a lower energy barrier separating the closed and open states of RyR1-FKBP12, and suggests that FKBP12 plays an important role by restricting conformations within RyR1's conformational landscape.

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Neuronal Ryanodine Receptors in Development and Aging

Cited by 63 publications

References 100 publications

Novel West syndrome candidate genes in a Chinese cohort

Novel West syndrome candidate genes in a Chinese cohort

Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes

The FKBP12 subunit modifies the long-range allosterism of the ryanodine receptor

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