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J. Biol. Chem., Vol. 282, Issue 48, 34828-34838, November 30, 2007

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Removal of FKBP12.6 Does Not Alter the Conductance and Activation of the Cardiac Ryanodine Receptor or the Susceptibility to Stress-induced Ventricular Arrhythmias^*

Jianmin Xiao, Xixi Tian, Peter P. Jones, Jeff Bolstad, Huihui Kong, Ruiwu Wang, Lin Zhang, Henry J. Duff¹, Anne M. Gillis¹, Sidney Fleischer, Michael Kotlikoff^¶, Julio A. Copello^||2, and S. R. Wayne Chen³

From the Libin Cardiovascular Institute of Alberta, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, T2N 4N1, Canada, Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37240, ^¶Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, and ^||Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62794

The 12.6-kDa FK506-binding protein (FKBP12.6) is considered to be a key regulator of the cardiac ryanodine receptor (RyR2), but its precise role in RyR2 function is complex and controversial. In the present study we investigated the impact of FKBP12.6 removal on the properties of the RyR2 channel and the propensity for spontaneous Ca²⁺ release and the occurrence of ventricular arrhythmias. Single channel recordings in lipid bilayers showed that FK506 treatment of recombinant RyR2 co-expressed with or without FKBP12.6 or native canine RyR2 did not induce long-lived subconductance states. [³H]Ryanodine binding studies revealed that coexpression with or without FKBP12.6 or treatment with or without FK506 did not alter the sensitivity of RyR2 to activation by Ca²⁺ or caffeine. Furthermore, single cell Ca²⁺ imaging analyses demonstrated that HEK293 cells co-expressing RyR2 and FKBP12.6 or expressing RyR2 alone displayed the same propensity for spontaneous Ca²⁺ release or store overload-induced Ca²⁺ release (SOICR). FK506 increased the amplitude and decreased the frequency of SOICR in HEK293 cells expressing RyR2 with or without FKBP12.6, indicating that the action of FK506 on SOICR is independent of FKBP12.6. As with recombinant RyR2, the conductance and ligand-gating properties of single RyR2 channels from FKBP12.6-null mice were indistinguishable from those of single wild type channels. Moreover, FKBP12.6-null mice did not exhibit enhanced susceptibility to stress-induced ventricular arrhythmias, in contrast to previous reports. Collectively, our results demonstrate that the loss of FKBP12.6 has no significant effect on the conduction and activation of RyR2 or the propensity for spontaneous Ca²⁺ release and stress-induced ventricular arrhythmias.

Received for publication, September 5, 2007 , and in revised form, October 2, 2007.

^* This work was supported in part by National Institutes of Health Research Grants RO1HL75210 (to S. R. W. C.) and a grant from the Canadian Institutes of Health Research (to S. R. W. C., H. J. D., and A. M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Alberta Heritage Foundation for Medical Research Scientists.

² Supported by National Institutes of Health R01GM078665.

³ To whom correspondence should be addressed: 3330 Hospital Drive N. W., Calgary, AB, Canada, T2N 4N1. Tel.: 403-220-4235; Fax: 403-281-4841; E-mail: swchen{at}ucalgary.ca.

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