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Abstract
Ryanodine receptor (RyR) Ca2+ channels are central to striated muscle function and influence signalling in neurons and other cell types. Beneficially low RyR activity and maximum conductance opening may be stabilised when RyRs bind to FK506 binding proteins (FKBPs) and destabilised by FKBP dissociation, with submaximal opening during RyR hyperactivity associated with myopathies and neurological disorders. However, the correlation with submaximal opening is debated and quantitative evidence is lacking. Here, we have measured altered FKBP binding to RyRs and submaximal activity with addition of wild-type (WT) CLIC2, an inhibitory RyR ligand, or its H101Q mutant that hyperactivates RyRs, which probably causes cardiac and intellectual abnormalities. The proportion of sub-conductance opening increases with WT and H101Q CLIC2 and is correlated with reduced FKBP-RyR association. The sub-conductance opening reduces RyR currents in the presence of WT CLIC2. In contrast, sub-conductance openings contribute to excess RyR 'leak' with H101Q CLIC2. There are significant FKBP and RyR isoform-specific actions of CLIC2, rapamycin and FK506 on FKBP-RyR association. The results show that FKBPs do influence RyR gating and would contribute to excess Ca2+ release in this CLIC2 RyR channelopathy.
Highlights
The Ryanodine receptor (RyR) ion channel releases Ca2+ from sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) Ca2+ stores and is essential for excitation–contraction coupling in skeletal muscle and the heart
Sub-state opening induced by WT CLIC2 and H101Q CLIC2 We previously reported that WT CLIC2 inhibits RyR1 and RyR2 channels and that the H101Q mutation in CLIC2 reverses the effect of the WT protein, causing channel hyperactivity (Takano et al, 2012)
The amplitude of levels varied from time to time in individual channels as well as between channels, both WT and H101Q CLIC2 enhanced the fraction of openings to these levels, irrespective of whether overall channel activity fell (WT) or increased (H101Q)
Summary
The RyR ion channel releases Ca2+ from sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) Ca2+ stores and is essential for excitation–contraction coupling in skeletal muscle and the heart. The main RyR isoforms expressed in skeletal muscle and in the heart are RyR1 and RyR2, respectively. The >2 MDa RyR homotetramer, with its associated proteins, forms a Ca2+-signalling complex that extends from the SR lumen through the cytoplasm to the extracellular space. It is regulated by numerous cytosolic factors. FKBP12 alone is expressed in skeletal muscle and binds to RyR1, whereas FKBP12 and FKBP12.6 are expressed in the heart and central nervous system in most species, and both are bound to RyR2 (Lanner et al, 2010). The association of FKBPs with RyRs impacts channel gating mechanisms and disruption of this interactions has been implicated in Ca2+ mishandling that underlies many cardiac and skeletal myopathies (Chelu et al, 2004; Bellinger et al, 2008)
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