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Biophysical Journal, Volume 72, Issue 1, 1 January 1997, Pages 146-162
G.P. Ahern, P.R. Junankar and A.F. Dulhunty
AbstractFKBP12 was removed from ryanodine receptors (RyRs) by incubation of rabbit skeletal muscle terminal cisternae membranes with rapamycin. The extent of FKBP12 removal was estimated by immunostaining Western blots of terminal cisternae proteins. Single FKBP12-depleted RyR channels, incorporated into planar lipid bilayers, were modulated by Ca2+, ATP, ryanodine, and ruthenium red in the cis chamber and opened frequently to the normal maximum conductance of approximately 230 pS and to substate levels of approximately 0.25, approximately 0.5, and approximately 0.75 of the maximum conductance. Substate activity was rarely seen in native RyRs. Ryanodine did not after the number of conductance levels in FKBP12-depleted channels, but, at a membrane potential of +40 mV, reduced both the maximum and the substate conductances by approximately 50%. FKBP12-stripped channels were activated by a 10-fold-lower [Ca2+] and inhibited by a 10-fold-higher [Ca2+], than RyRs from control-incubated and native terminal cisternae vesicles. The open probability (Po) of these FKBP12-deficient channels was greater than that of control channels at 0.1 microM and 1 mM cis Ca2+ but no different at 10 microM cis Ca2+, where channels showed maximal Ca2+ activation. The approximately 0.25 substate was less sensitive than the maximum conductance to inhibition by Ca2+ and was the dominant level in channels inhibited by 1 mM cis Ca2+. The results show that FKBP12 coordinates the gating of channel activity in control and ryanodine-modified RyRs.
Abstract | PDF (1866 kb) - Modulation of intracellular Ca levels in the heart by sorcin...Modulation of intracellular Ca levels in the heart by sorcin and FKBP12, two accessory proteins of ryanodine receptors
Trends in Pharmacological Sciences, Volume 19, Issue 12, 1 December 1998, Pages 479-483
Hector H. Valdivia
Full Text | PDF (194 kb) - Ca-Dependent Interaction between FKBP12 and Calcineurin Regu...Ca-Dependent Interaction between FKBP12 and Calcineurin Regulates Activity of the Ca Release Channel in Skeletal Muscle
Biophysical Journal, Volume 83, Issue 5, 1 November 2002, Pages 2539-2549
Dong Wook Shin, Zui Pan, Arun Bandyopadhyay, Manjunatha B. Bhat, Do Han Kim and Jianjie Ma
AbstractCalcineurin is a Ca and calmodulin-dependent protein phosphatase with diverse cellular functions. Here we examined the physical and functional interactions between calcineurin and ryanodine receptor (RyR) in a C2C12 cell line derived from mouse skeletal muscle. Coimmunoprecipitation experiments revealed that the association between RyR and calcineurin exhibits a strong Ca dependence. This association involves a Ca dependent interaction between calcineurin and FK506-binding protein (FKBP12), an accessory subunit of RyR. Pretreatment with cyclosporin A, an inhibitor of calcineurin, enhanced the caffeine-induced Ca release (CICR) in C2C12 cells. This effect was similar to those of FK506 and rapamycin, two drugs known to cause dissociation of FKBP12 from RyR. Overexpression of a constitutively active form of calcineurin in C2C12 cells, ΔCnA(391–521) (deletion of the last 131 amino acids from calcineurin), resulted in a decrease in CICR. This decrease in CICR activity was partially recovered by pretreatment with cyclosporin A. Furthermore, overexpression of an endogenous calcineurin inhibitor (cain) or an inactive form of calcineurin (ΔCnA(H101Q)) in C2C12 cells resulted in up-regulation of CICR. Taken together, our data suggest that a trimeric-interaction among calcineurin, FKBP12, and RyR is important for the regulation of the RyR channel activity and may play an important role in the Ca signaling of muscle contraction and relaxation.
Abstract | Full Text | PDF (316 kb) - …more
Copyright © 1995 The Biophysical Society. All rights reserved.
Biophysical Journal, Volume 69, Issue 6, 2398-2404, 1 December 1995
doi:10.1016/S0006-3495(95)80109-8
Research Article
Rectification of skeletal muscle ryanodine receptor mediated by FK506 binding protein
J. Ma, M.B. Bhat and J. Zhao
Abstract
The cytosolic receptor for immunosuppressant drugs, FK506 binding protein (FKBP12), maintains a tight association with ryanodine receptors of sarcoplasmic reticulum (SR) membrane in skeletal muscle. The interaction between FKBP12 and ryanodine receptors resulted in distinct rectification of the Ca release channel. The endogenous FKBP-bound Ca release channel conducted current unidirectionally from SR lumen to myoplasm; in the opposite direction, the channel deactivated with fast kinetics. The binding of FKBP12 is likely to alter subunit interactions within the ryanodine receptor complex, as revealed by changes in conductance states of the channel. Both on- and off-rates of FKBP12 binding to the ryanodine receptor showed clear dependence on the membrane potential, suggesting that the binding sites of FKBP12 reside in or near the conduction pore of the Ca release channel. Rectification of the Ca release channel would prevent counter-current flow during the rapid release of Ca from SR membrane, and thus may serve as a negative feedback mechanism that participates in the process of muscle excitation-contraction coupling.
