NDLI: Ablation of Skeletal Muscle Triadin Impairs FKBP12/RyR1 Channel Interactions Essential for Maintaining Resting Cytoplasmic Ca2+ *

Content Provider	PubMed Central
Author	Eltit, Jose M. Feng, Wei Lopez, Jose R. Padilla, Isela T. Pessah, Isaac N. Molinski, Tadeusz F. Fruen, Bradley R. Allen, Paul D. Perez, Claudio F.
Abstract	Previously, we have shown that lack of expression of triadins in skeletal muscle cells results in significant increase of myoplasmic resting free Ca2+ ([Ca2+]rest), suggesting a role for triadins in modulating global intracellular Ca2+ homeostasis. To understand this mechanism, we study here how triadin alters [Ca2+]rest, Ca2+ release, and Ca2+ entry pathways using a combination of Ca2+ microelectrodes, channels reconstituted in bilayer lipid membranes (BLM), Ca2+, and Mn2+ imaging analyses of myotubes and RyR1 channels obtained from triadin-null mice. Unlike WT cells, triadin-null myotubes had chronically elevated [Ca2+]rest that was sensitive to inhibition with ryanodine, suggesting that triadin-null cells have increased basal RyR1 activity. Consistently, BLM studies indicate that, unlike WT-RyR1, triadin-null channels more frequently display atypical gating behavior with multiple and stable subconductance states. Accordingly, pulldown analysis and fluorescent FKBP12 binding studies in triadin-null muscles revealed a significant impairment of the FKBP12/RyR1 interaction. Mn2+ quench rates under resting conditions indicate that triadin-null cells also have higher Ca2+ entry rates and lower sarcoplasmic reticulum Ca2+ load than WT cells. Overexpression of FKBP12.6 reverted the null phenotype, reducing resting Ca2+ entry, recovering sarcoplasmic reticulum Ca2+ content levels, and restoring near normal [Ca2+]rest. Exogenous FKBP12.6 also reduced the RyR1 channel P o but did not rescue subconductance behavior. In contrast, FKBP12 neither reduced P o nor recovered multiple subconductance gating. These data suggest that elevated [Ca2+]rest in triadin-null myotubes is primarily driven by dysregulated RyR1 channel activity that results in part from impaired FKBP12/RyR1 functional interactions and a secondary increased Ca2+ entry at rest.
Related Links	http://dx.doi.org/10.1074/jbc.M110.164525
Starting Page	38453
File Format	PDF
ISSN	1083351X
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	49
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-12-03
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Ablation of Skeletal Muscle Triadin Impairs FKBP12/RyR1 Channel Interactions Essential for Maintaining Resting Cytoplasmic Ca2+

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Ablation of Skeletal Muscle Triadin Impairs FKBP12/RyR1 Channel Interactions Essential for Maintaining Resting Cytoplasmic Ca2+ *

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