Effects of Conformational Peptide Probe DP4 on Bidirectional Signaling between DHPR and RyR1 Calcium Channels in Voltage-Clamped Skeletal Muscle Fibers

Olojo, Rotimi; Hernández‐Ochoa, Erick O.; Ikemoto, Noriaki; Schneider, Martin F.

doi:10.1016/j.bpj.2011.04.012

Cited by 8 publications

(19 citation statements)

References 59 publications

(89 reference statements)

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“…High-speed fluo-4 fluorescence confocal microscopy measurements were carried out on a Zeiss LSM 5 Live system as previously described (32,38). Fibers were loaded with fluo-4 AM (Invitrogen) at 2 M for 30 min at 22°C.…”

Section: Animalsmentioning

confidence: 99%

NOX2-dependent ROS is required for HDAC5 nuclear efflux and contributes to HDAC4 nuclear efflux during intense repetitive activity of fast skeletal muscle fibers

Hernández‐Ochoa

Randall

Schneider

2012

American Journal of Physiology-Cell Physiology

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Reactive oxygen species (ROS) have been linked to oxidation and nuclear efflux of class IIa histone deacetylase 4 (HDAC4) in cardiac muscle. Here we use HDAC-GFP fusion proteins expressed in isolated adult mouse flexor digitorum brevis muscle fibers to study ROS mediation of HDAC localization in skeletal muscle. H(2)O(2) causes nuclear efflux of HDAC4-GFP or HDAC5-GFP, which is blocked by the ROS scavenger N-acetyl-l-cysteine (NAC). Repetitive stimulation with 100-ms trains at 50 Hz, 2/s ("50-Hz trains") increased ROS production and caused HDAC4-GFP or HDAC5-GFP nuclear efflux. During 50-Hz trains, HDAC5-GFP nuclear efflux was completely blocked by NAC, but HDAC4-GFP nuclear efflux was only partially blocked by NAC and partially blocked by the calcium-dependent protein kinase (CaMK) inhibitor KN-62. Thus, during intense activity both ROS and CaMK play roles in nuclear efflux of HDAC4, but only ROS mediates HDAC5 nuclear efflux. The 10-Hz continuous stimulation did not increase the rate of ROS production and did not cause HDAC5-GFP nuclear efflux but promoted HDAC4-GFP nuclear efflux that was sensitive to KN-62 but not NAC and thus mediated by CaMK but not by ROS. Fibers from NOX2 knockout mice lacked ROS production and ROS-dependent nuclear efflux of HDAC5-GFP or HDAC4-GFP during 50-Hz trains but had unmodified Ca(2+) transients. Our results demonstrate that ROS generated by NOX2 could play important roles in muscle remodeling due to intense muscle activity and that the nuclear effluxes of HDAC4 and HDAC5 are differentially regulated by Ca(2+) and ROS during muscle activity.

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Section: Animalsmentioning

confidence: 99%

NOX2-dependent ROS is required for HDAC5 nuclear efflux and contributes to HDAC4 nuclear efflux during intense repetitive activity of fast skeletal muscle fibers

Hernández‐Ochoa

Randall

Schneider

2012

American Journal of Physiology-Cell Physiology

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“…Brief electrical field stimuli were applied by 2 parallel platinum wires to elicit Ca 2+ transients triggered by action potentials. Transients were also recorded from fibers voltage clamped in the whole cell patch mode, as previously described (40). sensitive optical methods did not detect a defect in myoplasmic Ca 2+ transients in human R528H fibers or mdg myotubes transfected with Ca V 1.1 R528H (34).…”

Section: Figurementioning

confidence: 99%

A calcium channel mutant mouse model of hypokalemic periodic paralysis

Hernández‐Ochoa

et al. 2012

J. Clin. Invest.

131

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Hypokalemic periodic paralysis (HypoPP) is a familial skeletal muscle disorder that presents with recurrent episodes of severe weakness lasting hours to days associated with reduced serum potassium (K + ). HypoPP is genetically heterogeneous, with missense mutations of a calcium channel (Ca V 1.1) or a sodium channel (Na V 1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between Ca V 1.1 mutations and the ictal loss of muscle excitability during an attack of weakness in HypoPP is unknown. To address this question, we developed a mouse model for HypoPP with a targeted Ca V 1.1 R528H mutation. The Ca v 1.1 R528H mice had a HypoPP phenotype for which low K + challenge produced a paradoxical depolarization of the resting potential, loss of muscle excitability, and weakness. A vacuolar myopathy with dilated transverse tubules and disruption of the triad junctions impaired Ca 2+ release and likely contributed to the mild permanent weakness. Fibers from the Ca V 1.1 R528H mouse had a small anomalous inward current at the resting potential, similar to our observations in the Na V 1.4 R669H HypoPP mouse model. This "gating pore current" may be a common mechanism for paradoxical depolarization and susceptibility to HypoPP arising from missense mutations in the S4 voltage sensor of either calcium or sodium channels.

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“…The II-III loop of the α1 subunit is critical for orthograde signaling to RyR1 in response to DHPR voltage-gated activation [98] and also enhances DHPR function via retrograde signaling from RyR1 to the DHPR [97, 104]. Orthograde signaling results in the release of Ca ++ from the sarcoplasmic reticulum through the RyR1 ion channel.…”

Section: Introductionmentioning

confidence: 99%

“…Group 1 Pathomechanisms: CCD/MH: Mutations in the RyR1 N-terminal and central domains that disrupt FKBP12-RyR1 interaction are proposed to result in MH [65, 104] or CCD/MH [104]. V2461G and V2461I are RyR1 mutations that disrupt FKBP12 binding.…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that RyR1 conformational change in response to DHPR activation leads to RyR1 intrinsic modulation of the opening/closing of the RyR1 ion channel. This intrinsic modulation is based on inter-domain interaction where the RyR1 central domain (Leu 2442 -Pro 2477 ) interacts with the RyR1 N-terminal domain [104]. This interdomain interaction is regulated by CaM and Ca ++ levels regulate the function of CaM.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Review of RyR1 pathway and associated pathomechanisms

Witherspoon

Meilleur

2016

acta neuropathol commun

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Ryanodine receptor isoform-1 (RyR1) is a major calcium channel in skeletal muscle important for excitation-contraction coupling. Mutations in the RYR1 gene yield RyR1 protein dysfunction that manifests clinically as RYR1-related congenital myopathies (RYR1-RM) and/or malignant hyperthermia susceptibility (MHS). Individuals with RYR1-RM and/or MHS exhibit varying symptoms and severity. The symptoms impair quality of life and put patients at risk for early mortality, yet the cause of varying severity is not well understood. Currently, there is no Food and Drug Administration (FDA) approved treatment for RYR1-RM. Discovery of effective treatments is therefore critical, requiring knowledge of the RyR1 pathway. The purpose of this review is to compile work published to date on the RyR1 pathway and to implicate potential regions as targets for treatment. The RyR1 pathway is comprised of protein-protein interactions, protein-ligand interactions, and post-translational modifications, creating an activation/regulatory macromolecular complex. Given the complexity of this pathway, we divided these interactions and modifications into six regulatory groups. Three of several RyR1 interacting proteins, FK506-binding protein 12 (FKBP12), triadin, and calmodulin, were identified as playing important roles across all groups and may serve as promising target sites for treatment. Also, variability in disease severity may be influenced by prolongation or hyperactivity of post-translational modifications resulting from RyR1 dysfunction.

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Effects of Conformational Peptide Probe DP4 on Bidirectional Signaling between DHPR and RyR1 Calcium Channels in Voltage-Clamped Skeletal Muscle Fibers

Cited by 8 publications

References 59 publications

NOX2-dependent ROS is required for HDAC5 nuclear efflux and contributes to HDAC4 nuclear efflux during intense repetitive activity of fast skeletal muscle fibers

NOX2-dependent ROS is required for HDAC5 nuclear efflux and contributes to HDAC4 nuclear efflux during intense repetitive activity of fast skeletal muscle fibers

A calcium channel mutant mouse model of hypokalemic periodic paralysis

Review of RyR1 pathway and associated pathomechanisms

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