Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies

Xu, Le; Wang, Ying; Yamaguchi, Naohiro; Pasek, Daniel A.; Meissner, Gerhard

doi:10.1074/jbc.m707353200

Cited by 37 publications

(34 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, ryanodine receptor heterotetramers show an altered conductance state, with a behavior intermediate to those of the homomeric channels, and an altered Ca 2+ selectivity (24). Within heteromeric inositol 1,4,5-trisphosphate receptor complexes, each subunit individually contributes to the overall receptor ligand affinity (25–28).…”

Section: Discussionmentioning

confidence: 99%

Two-pore Channels Form Homo- and Heterodimers

Rietdorf¹,

Funnell²,

Ruas

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Two-pore channels (TPCs) are part of the NAADP-receptor complex, but how and whether they dimerize are unclear.Results: Human TPCs form homo- and heteromeric complexes.Conclusion: Multimerization can regulate function and localization of TPCs.Significance: Multimerization of TPCs is likely to affect fusion events in the endolysosomal system, disturbances of which can lead to the development of lysosomal storage diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Two-pore Channels Form Homo- and Heterodimers

Rietdorf¹,

Funnell²,

Ruas

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…A recent study of the single channel properties of mutant RyR1 (36) has shown that functional variability is an intrinsic feature of Ca 2ϩ release channels expressed in the heterozygous state. It was then proposed that the random combination of WT and mutant subunits in an RyR1 tetramer might contribute to phenotypic variability in RyR1-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Zvaritch

Kraeva

Bombardier

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Ryr1 I4895T/wt (IT/؉) mice express a knockin mutation corresponding to the human I4898T EC-uncoupling mutation in the type 1 ryanodine receptor/Ca 2؉ release channel (RyR1), which causes a severe form of central core disease (CCD). IT/؉ mice exhibit a slowly progressive congenital myopathy, with neonatal respiratory stress, skeletal muscle weakness, impaired mobility, dorsal kyphosis, and hind limb paralysis. Lesions observed in myofibers from diseased mice undergo age-dependent transformation from minicores to cores and nemaline rods. Early ultrastructural abnormalities include sarcomeric misalignment, Z-line streaming, focal loss of cross-striations, and myofibrillar splitting and intermingling that may arise from defective myofibrillogenesis. However, manifestation of the disease phenotype is highly variable on a Sv129 genomic background. Quantitative RT-PCR shows an equimolar ratio of WT and mutant Ryr1 transcripts within IT/؉ myofibers and total RyR1 protein expression levels are normal. We propose a unifying theory in which the cause of core formation lies in functional heterogeneity among RyR1 tetramers. Random combinations of normal and either leaky or EC-uncoupled RyR subunits would lead to spatial differences in Ca 2؉ transients; the resulting heterogeneity of contraction among myofibrils would lead to focal, irreversible tearing and shearing, which would, over time, enlarge to form minicores, cores, and nemaline rods. The IT/؉ mouse line is proposed to be a valid model of RyR1-related congenital myopathy, offering high potential for elucidation of the pathogenesis of skeletal muscle disorders arising from impaired EC coupling.calcium ͉ central core disease ͉ multiminicore disease ͉ nemaline rod myopathy ͉ ryanodine receptor

show abstract

“…c Control experiment to show that PCR reaction was not saturated at 35 cycles and that differences seen in band density are a true reflection of amounts of ASI(+)RyR1 and ASI(−)RyR1 mRNA in the muscle. Representative samples with ASI(+) product less that ASI(−), ASI(+) product equal to ASI(−) product, and ASI(+) product more than ASI(−) product were selected and a PCR of 28 cycles, b PCR of 32 cycles, and c PCR of 35 cycles performed et al [35] showed that the co-expression of WT RyR1 and a mutant RyR1 in HEK cells produced RyR1s that exhibited a range of phenotypes intermediate between the WT phenotype and the mutant [35]. If RyR1 contained both ASI(+) and ASI(−) subunits, the channels would display a range of characteristics between those of homotetrameric ASI(+)RyR1 and ASI(−)RyR1 channels that could fine-tune the characteristics of EC coupling in individual fibers.…”

Section: Discussionmentioning

confidence: 99%

Unexpected dependence of RyR1 splice variant expression in human lower limb muscles on fiber-type composition

Willemse

Theodoratos

Smith

et al. 2015

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

The skeletal muscle ryanodine receptor Ca(2+) release channel (RyR1), essential for excitation-contraction (EC) coupling, demonstrates a known developmentally regulated alternative splicing in the ASI region. We now find unexpectedly that the expression of the splice variants is closely related to fiber type in adult human lower limb muscles. We examined the distribution of myosin heavy chain isoforms and ASI splice variants in gluteus minimus, gluteus medius and vastus medialis from patients aged 45 to 85 years. There was a strong positive correlation between ASI(+)RyR1 and the percentage of type 2 fibers in the muscles (r = 0.725), and a correspondingly strong negative correlation between the percentages of ASI(+)RyR1 and percentage of type 1 fibers. When the type 2 fiber data were separated into type 2X and type 2A, the correlation with ASI(+)RyR1 was stronger in type 2X fibers (r = 0.781) than in type 2A fibers (r = 0.461). There was no significant correlation between age and either fiber-type composition or ASI(+)RyR1/ASI(-)RyR1 ratio. The results suggest that the reduced expression of ASI(-)RyR1 during development may reflect a reduction in type 1 fibers during development. Preferential expression of ASI(-) RyR1, having a higher gain of in Ca(2+) release during EC coupling than ASI(+)RyR1, may compensate for the reduced terminal cisternae volume, fewer junctional contacts and reduced charge movement in type 1 fibers.

show abstract

Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies

Cited by 37 publications

References 37 publications

Two-pore Channels Form Homo- and Heterodimers

Two-pore Channels Form Homo- and Heterodimers

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Unexpected dependence of RyR1 splice variant expression in human lower limb muscles on fiber-type composition

Contact Info

Product

Resources

About

Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies

Cited by 37 publications

References 37 publications

Two-pore Channels Form Homo- and Heterodimers

Two-pore Channels Form Homo- and Heterodimers

Ca 2+ dysregulation in Ryr1 I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Unexpected dependence of RyR1 splice variant expression in human lower limb muscles on fiber-type composition

Contact Info

Product

Resources

About

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods