FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6.

PloS One
Elena GalfréR Sitsapesan

Abstract

Changes in FKBP12.6 binding to cardiac ryanodine receptors (RyR2) are implicated in mediating disturbances in Ca(2+)-homeostasis in heart failure but there is controversy over the functional effects of FKBP12.6 on RyR2 channel gating. We have therefore investigated the effects of FKBP12.6 and another structurally similar molecule, FKBP12, which is far more abundant in heart, on the gating of single sheep RyR2 channels incorporated into planar phospholipid bilayers and on spontaneous waves of Ca(2+)-induced Ca(2+)-release in rat isolated permeabilised cardiac cells. We demonstrate that FKBP12 is a high affinity activator of RyR2, sensitising the channel to cytosolic Ca(2+), whereas FKBP12.6 has very low efficacy, but can antagonise the effects of FKBP12. Mathematical modelling of the data shows the importance of the relative concentrations of FKBP12 and FKBP12.6 in determining RyR2 activity. Consistent with the single-channel results, physiological concentrations of FKBP12 (3 µM) increased Ca(2+)-wave frequency and decreased the SR Ca(2+)-content in cardiac cells. FKBP12.6, itself, had no effect on wave frequency but antagonised the effects of FKBP12.We provide a biophysical analysis of the mechanisms by which FK-binding protein...Continue Reading

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Citations

Sep 21, 2013·Fish Physiology and Biochemistry·Hanna Korajoki, Matti Vornanen
Feb 15, 2013·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Jeong-Heon LeeJorge P Figueroa
Aug 20, 2014·Journal of Molecular Biology·Filip Van Petegem
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Methods Mentioned

BETA
PCR
size exclusion chromatography
gel filtration
electrophoresis

Software Mentioned

ImageJ
IGOR Pro
Xcalibar
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