© 1996 American Heart Association, Inc.
Articles |
Effects of Rapamycin on Ryanodine Receptor/Ca2+-Release Channels From Cardiac Muscle
From the Departments of Physiology and Medicine (E.K., B.E.E.), University of Connecticut, Farmington, and the Department of Medicine and Brookdale Center for Molecular Biology (A.R.M.), Mount Sinai School of Medicine, New York, NY.
Correspondence to Dr Edward Kaftan, Laboratory of Molecular Hermeneutics, Department of Physiology, University of Connecticut, 263 Farmington Ave, Farmington, CT 06030-3505. E-mail ekaftan@neuron.uchc.edu.
Abstract Ryanodine receptors (RyRs) are intracellular channels that regulate the release of Ca2+ from the endoplasmic reticulum of many cell types. The RyRs are physically associated with FK506-binding proteins (FKBPs); immunophilins, with cis-trans peptidyl-prolyl isomerase activity. FKBP12 copurifies with RyR1 (skeletal isoform) and modulates its gating. A different form of FKBP with a slightly higher molecular weight copurifies with RyR2 (cardiac isoform). Previous studies have demonstrated that FKBP stabilizes gating of the skeletal Ca2+-release channel. In the present study, we measured the activity of cardiac RyRs incorporated into planar lipid bilayers to show that rapamycin, a drug that inhibits the prolyl isomerase activity of FKBP and dissociates FKBP from the RyR, increases the open probability and reduces the current amplitude of cardiac muscle Ca2+-release channels. These experiments show for the first time that submicromolar concentrations of rapamycin can alter channel function. Our results provide support for the hypotheses that FKBP functionally associates with the RyR and that the immunosuppressant drug, rapamycin, alters the function of both cardiac and skeletal muscle isoforms of the Ca2+-release channel. Our findings suggest that FKBP-dependent modulation of channel function may be generally applicable to all members of the intracellular Ca2+-release channel family and that FKBPs may play important regulatory roles in many cell processes, ranging from long-term depression in neurons to contractility in cardiomyocytes.
Key Words: intracellular channels • immunosuppressive therapy • FK506 • FK506-binding protein
This article has been cited by other articles:
 |
|
 |
|
  J. R. H. Mauban, M. O'Donnell, S. Warrier, S. Manni, and M. Bond AKAP-Scaffolding Proteins and Regulation of Cardiac Physiology Physiology, April 1, 2009; 24(2): 78 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Xiao, X. Tian, P. P. Jones, J. Bolstad, H. Kong, R. Wang, L. Zhang, H. J. Duff, A. M. Gillis, S. Fleischer, et al. Removal of FKBP12.6 Does Not Alter the Conductance and Activation of the Cardiac Ryanodine Receptor or the Susceptibility to Stress-induced Ventricular Arrhythmias J. Biol. Chem., November 30, 2007; 282(48): 34828 - 34838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Meng, B. Xiao, S. Cai, X. Huang, F. Li, J. Bolstad, R. Trujillo, J. Airey, S. R. W. Chen, T. Wagenknecht, et al. Three-Dimensional Localization of Serine 2808, a Phosphorylation Site in Cardiac Ryanodine Receptor J. Biol. Chem., August 31, 2007; 282(35): 25929 - 25939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Long, L. G. Cook, G.-Y. Wu, and B. M. Mitchell Removal of Fkbp12/12.6 From Endothelial Ryanodine Receptors Leads to an Intracellular Calcium Leak and Endothelial Dysfunction Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1580 - 1586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Katra, T. Oya, G. S. Hoeker, and K. R. Laurita Ryanodine receptor dysfunction and triggered activity in the heart Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2144 - H2151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Long, L. G. Cook, S. L. Hamilton, G.-Y. Wu, and B. M. Mitchell FK506 Binding Protein 12/12.6 Depletion Increases Endothelial Nitric Oxide Synthase Threonine 495 Phosphorylation and Blood Pressure Hypertension, March 1, 2007; 49(3): 569 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Huang, J. Shan, S. Reiken, X. H. T. Wehrens, and A. R. Marks Analysis of calstabin2 (FKBP12.6)-ryanodine receptor interactions: Rescue of heart failure by calstabin2 in mice PNAS, February 28, 2006; 103(9): 3456 - 3461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Creighton, R. Virmani, R. Kutys, and A. Burke Identification of Novel Missense Mutations of Cardiac Ryanodine Receptor Gene in Exercise-Induced Sudden Death at Autopsy J. Mol. Diagn., February 1, 2006; 8(1): 62 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. H. T. Wehrens, S. E. Lehnart, S. Reiken, J. A. Vest, A. Wronska, and A. R. Marks Inaugural Article: Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression PNAS, January 17, 2006; 103(3): 511 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Hidalgo Cross talk between Ca2+ and redox signalling cascades in muscle and neurons through the combined activation of ryanodine receptors/Ca2+ release channels Phil Trans R Soc B, December 29, 2005; 360(1464): 2237 - 2246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Ai, J. W. Curran, T. R. Shannon, D. M. Bers, and S. M. Pogwizd Ca2+/Calmodulin-Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphorylation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure Circ. Res., December 9, 2005; 97(12): 1314 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Goonasekera, S. R. W. Chen, and R. T. Dirksen Reconstitution of local Ca2+ signaling between cardiac L-type Ca2+ channels and ryanodine receptors: insights into regulation by FKBP12.6 Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1476 - C1484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Fauconnier, A. Lacampagne, J.-M. Rauzier, G. Vassort, and S. Richard Ca2+-dependent reduction of IK1 in rat ventricular cells: A novel paradigm for arrhythmia in heart failure? Cardiovasc Res, November 1, 2005; 68(2): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Zahradnik, S. Gyorke, and A. Zahradnikova Calcium Activation of Ryanodine Receptor Channels--Reconciling RyR Gating Models with Tetrameric Channel Structure J. Gen. Physiol., October 31, 2005; 126(5): 515 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Balasubramaniam, S. Chawla, A. A. Grace, and C. L.-H. Huang Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca2+ homeostasis Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1584 - H1593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. H. T. Wehrens, S. E. Lehnart, S. Reiken, R. van der Nagel, R. Morales, J. Sun, Z. Cheng, S.-X. Deng, L. J. de Windt, D. W. Landry, et al. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure PNAS, July 5, 2005; 102(27): 9607 - 9612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Fritz, N. Macrez, J. Mironneau, L. H. Jeyakumar, S. Fleischer, and J.-L. Morel Ryanodine receptor subtype 2 encodes Ca2+ oscillations activated by acetylcholine via the M2 muscarinic receptor/cADP-ribose signalling pathway in duodenum myocytes J. Cell Sci., May 15, 2005; 118(10): 2261 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Gomez, I. Schuster, J. Fauconnier, J. Prestle, G. Hasenfuss, and S. Richard FKBP12.6 overexpression decreases Ca2+ spark amplitude but enhances [Ca2+]i transient in rat cardiac myocytes Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1987 - H1993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bagattin, C. Veronese, B. Bauce, W. Wuyts, L. Settimo, A. Nava, A. Rampazzo, and G. A. Danieli Denaturing HPLC-Based Approach for Detecting RYR2 Mutations Involved in Malignant Arrhythmias Clin. Chem., July 1, 2004; 50(7): 1148 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. H. Lee, S.-H. Rho, S.-J. Kwon, S. H. Eom, P. D. Allen, and D. H. Kim N-terminal Region of FKBP12 Is Essential for Binding to the Skeletal Ryanodine Receptor J. Biol. Chem., June 18, 2004; 279(25): 26481 - 26488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Loughrey, T. Seidler, S. L. W. Miller, J. Prestle, K. E. MacEachern, D. F. Reynolds, G. Hasenfuss, and G. L. Smith Over-expression of FK506-binding protein FKBP12.6 alters excitation-contraction coupling in adult rabbit cardiomyocytes J. Physiol., May 1, 2004; 556(3): 919 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Ginsburg and D. M. Bers Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger J. Physiol., April 15, 2004; 556(2): 463 - 480. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. H. T. Wehrens, S. E. Lehnart, S. R. Reiken, S.-X. Deng, J. A. Vest, D. Cervantes, J. Coromilas, D. W. Landry, and A. R. Marks Protection from Cardiac Arrhythmia Through Ryanodine Receptor-Stabilizing Protein Calstabin2 Science, April 9, 2004; 304(5668): 292 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Xiao, C. Sutherland, M. P. Walsh, and S.R. W. Chen Protein Kinase A Phosphorylation at Serine-2808 of the Cardiac Ca2+-Release Channel (Ryanodine Receptor) Does Not Dissociate 12.6-kDa FK506-Binding Protein (FKBP12.6) Circ. Res., March 5, 2004; 94(4): 487 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-X. Wang, Y.-M. Zheng, Q.-B. Mei, Q.-S. Wang, M. L. Collier, S. Fleischer, H.-B. Xin, and M. I. Kotlikoff FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells Am J Physiol Cell Physiol, March 1, 2004; 286(3): C538 - C546. [Abstract] [Full Text]
|
|
|
|
|
|
G. I. Anyatonwu, E. D. Buck, and B. E. Ehrlich Methanethiosulfonate Ethylammonium Block of Amine Currents through the Ryanodine Receptor Reveals Single Pore Architecture J. Biol. Chem., November 14, 2003; 278(46): 45528 - 45538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Bers, D. A. Eisner, and H. H. Valdivia Sarcoplasmic Reticulum Ca2+ and Heart Failure: Roles of Diastolic Leak and Ca2+ Transport Circ. Res., September 19, 2003; 93(6): 487 - 490. [Full Text] [PDF]
|
|
|
|
|
|
C. H. George, G. V. Higgs, J. J. Mackrill, and F. A. Lai Dysregulated Ryanodine Receptors Mediate Cellular Toxicity: RESTORATION OF NORMAL PHENOTYPE BY FKBP12.6 J. Biol. Chem., August 1, 2003; 278(31): 28856 - 28864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bull, J. J. Marengo, J. P. Finkelstein, M. I. Behrens, and O. Alvarez SH oxidation coordinates subunits of rat brain ryanodine receptor channels activated by calcium and ATP Am J Physiol Cell Physiol, July 1, 2003; 285(1): C119 - C128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Avila, E. H. Lee, C. F. Perez, P. D. Allen, and R. T. Dirksen FKBP12 Binding to RyR1 Modulates Excitation-Contraction Coupling in Mouse Skeletal Myotubes J. Biol. Chem., June 13, 2003; 278(25): 22600 - 22608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Reiken, X. H.T. Wehrens, J. A. Vest, A. Barbone, S. Klotz, D. Mancini, D. Burkhoff, and A. R. Marks {beta}-Blockers Restore Calcium Release Channel Function and Improve Cardiac Muscle Performance in Human Heart Failure Circulation, May 20, 2003; 107(19): 2459 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Marks A Guide for the Perplexed: Towards an Understanding of the Molecular Basis of Heart Failure Circulation, March 25, 2003; 107(11): 1456 - 1459. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Reiken, A. Lacampagne, H. Zhou, A. Kherani, S. E. Lehnart, C. Ward, F. Huang, M. Gaburjakova, J. Gaburjakova, N. Rosemblit, et al. PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure J. Cell Biol., March 17, 2003; 160(6): 919 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Reiken, M. Gaburjakova, S. Guatimosim, A. M. Gomez, J. D'Armiento, D. Burkhoff, J. Wang, G. Vassort, W. J. Lederer, and A. R. Marks Protein Kinase A Phosphorylation of the Cardiac Calcium Release Channel (Ryanodine Receptor) in Normal and Failing Hearts. ROLE OF PHOSPHATASES AND RESPONSE TO ISOPROTERENOL J. Biol. Chem., January 3, 2003; 278(1): 444 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Su, K. Sugishita, F. Li, M. Ritter, and W. H. Barry Effects of FK506 on [Ca2+]i Differ in Mouse and Rabbit Ventricular Myocytes J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 334 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Jiang, A. J. Lokuta, E. F. Farrell, M. R. Wolff, R. A. Haworth, and H. H. Valdivia Abnormal Ca2+ Release, but Normal Ryanodine Receptors, in Canine and Human Heart Failure Circ. Res., November 29, 2002; 91(11): 1015 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fill and J. A. Copello Ryanodine Receptor Calcium Release Channels Physiol Rev, October 1, 2002; 82(4): 893 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes Circ. Res., February 22, 2002; 90(3): 309 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.H.T. WEHRENS and A.R. MARKS Myocardial Disease in Failing Hearts: Defective Excitation-Contraction Coupling Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 533 - 542. [Abstract] [PDF]
|
|
|
|
|
|
S. Reiken, M. Gaburjakova, J. Gaburjakova, K.-l. He, A. Prieto, E. Becker, G.-h. Yi, J. Wang, D. Burkhoff, and A. R. Marks {beta}-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure Circulation, December 4, 2001; 104(23): 2843 - 2848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. H. Valdivia Cardiac Ryanodine Receptors and Accessory Proteins: Augmented Expression Does Not Necessarily Mean Big Function Circ. Res., February 2, 2001; 88(2): 134 - 136. [Full Text] [PDF]
|
|
|
|
|
|
J. Prestle, P. M.L. Janssen, A. P. Janssen, O. Zeitz, S. E. Lehnart, L. Bruce, G. L. Smith, and G. Hasenfuss Overexpression of FK506-Binding Protein FKBP12.6 in Cardiomyocytes Reduces Ryanodine Receptor-Mediated Ca2+ Leak From the Sarcoplasmic Reticulum and Increases Contractility Circ. Res., February 2, 2001; 88(2): 188 - 194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ono, M. Yano, T. Ohkusa, M. Kohno, T. Hisaoka, T. Tanigawa, S. Kobayashi, M. Kohno, and M. Matsuzaki Altered interaction of FKBP12.6 with ryanodine receptor as a cause of abnormal Ca2+ release in heart failure Cardiovasc Res, November 1, 2000; 48(2): 323 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yano, K. Ono, T. Ohkusa, M. Suetsugu, M. Kohno, T. Hisaoka, S. Kobayashi, Y. Hisamatsu, T. Yamamoto, M. Kohno, et al. Altered Stoichiometry of FKBP12.6 Versus Ryanodine Receptor as a Cause of Abnormal Ca2+ Leak Through Ryanodine Receptor in Heart Failure Circulation, October 24, 2000; 102(17): 2131 - 2136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. H. DuBell, W. J. Lederer, and T. B. Rogers K+ currents responsible for repolarization in mouse ventricle and their modulation by FK-506 and rapamycin Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H886 - H897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kanoh, M. Kondo, J. Tamaoki, H. Shirakawa, K. Aoshiba, S. Miyazaki, H. Kobayashi, N. Nagata, and A. Nagai Effect of FK506 on ATP-induced intracellular calcium oscillations in cow tracheal epithelium Am J Physiol Lung Cell Mol Physiol, June 1, 1999; 276(6): L891 - L899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M Bers and E. Perez-Reyes Ca channels in cardiac myocytes: structure and function in Ca influx and intracellular Ca release Cardiovasc Res, May 1, 1999; 42(2): 339 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Stern, L.-S. Song, H. Cheng, J. S.K. Sham, H. T. Yang, K. R. Boheler, and E. Rios Local Control Models of Cardiac Excitation-Contraction Coupling: A Possible Role for Allosteric Interactions between Ryanodine Receptors J. Gen. Physiol., March 1, 1999; 113(3): 469 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Park, T. K. Kim, and D. H. Kim Cyclosporin A treatment alters characteristics of Ca2+-release channel in cardiac sarcoplasmic reticulum Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H865 - H872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. H. duBell, S. T. Gaa, W. J. Lederer, and T. B. Rogers Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2041 - H2052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Meyers, T. S. Puri, A. J. Chien, T. Gao, P.-H. Hsu, M. M. Hosey, and G. I. Fishman Sorcin Associates with the Pore-forming Subunit of Voltage-dependent L-type Ca2+ Channels J. Biol. Chem., July 24, 1998; 273(30): 18930 - 18935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.A Eisner, A.W Trafford, M.E Dnaz, C.L Overend, and S.C O'Neill The control of Ca release from the cardiac sarcoplasmic reticulum: regulation versus autoregulation Cardiovasc Res, June 1, 1998; 38(3): 589 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Quinn, L. Castellani, K. Ondrias, and B. E. Ehrlich Characterization of the ryanodine receptor/channel of invertebrate muscle Am J Physiol Regulatory Integrative Comp Physiol, February 1, 1998; 274(2): R494 - R502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zucchi and S. Ronca-Testoni The Sarcoplasmic Reticulum Ca2+ Channel/Ryanodine Receptor: Modulation by Endogenous Effectors, Drugs and Disease States Pharmacol. Rev., March 1, 1997; 49(1): 1 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. McCall, L. Li, H. Satoh, T. R. Shannon, L. A. Blatter, and D. M. Bers Effects of FK-506 on Contraction and Ca2+ Transients in Rat Cardiac Myocytes Circ. Res., December 1, 1996; 79(6): 1110 - 1121. [Abstract] [Full Text]
|
|
|
|
|
|
M. Gaburjakova, J. Gaburjakova, S. Reiken, F. Huang, S. O. Marx, N. Rosemblit, and A. R. Marks FKBP12 Binding Modulates Ryanodine Receptor Channel Gating J. Biol. Chem., May 11, 2001; 276(20): 16931 - 16935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes Circ. Res., February 22, 2002; 90(3): 309 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. O. Marx, J. Gaburjakova, M. Gaburjakova, C. Henrikson, K. Ondrias, and A. R. Marks Coupled Gating Between Cardiac Calcium Release Channels (Ryanodine Receptors) Circ. Res., June 8, 2001; 88(11): 1151 - 1158. [Abstract] [Full Text] [PDF]
|
|