|
|
|
|
|
|
|
||
The Pore Region of the Skeletal Muscle Ryanodine Receptor Is a Primary Locus for Excitation-Contraction Uncoupling in Central Core Disease
2 Department of Biomedical Sciences, Colorado State University, Ft. Collins, CO 80523
3 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
Address correspondence to Robert Dirksen, Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642. Fax: (585) 273-2652; E-mail: Robert_Dirksen{at}URMC.rochester.edu
Human central core disease (CCD) is caused by mutations/deletions in the gene that encodes the skeletal muscle ryanodine receptor (RyR1). Previous studies have shown that CCD mutations in the NH2-terminal region of RyR1 lead to the formation of leaky SR Ca2+ release channels when expressed in myotubes derived from RyR1-knockout (dyspedic) mice, whereas a COOH-terminal mutant (I4897T) results in channels that are not leaky to Ca2+ but lack depolarization-induced Ca2+ release (termed excitation-contraction [EC] uncoupling). We show here that store depletion resulting from NH2-terminal (Y523S) and COOH-terminal (Y4795C) leaky CCD mutant release channels is eliminated after incorporation of the I4897T mutation into the channel (Y523S/I4897T and Y4795C/I4897T). In spite of normal SR Ca2+ content, myotubes expressing the double mutants lacked voltage-gated Ca2+ release and thus exhibited an EC uncoupling phenotype similar to that of I4897T-expressing myotubes. We also show that dyspedic myotubes expressing each of seven recently identified CCD mutations located in exon 102 of the RyR1 gene (G4890R, R4892W, I4897T, G4898E, G4898R, A4905V, R4913G) behave as EC-uncoupled release channels. Interestingly, voltage-gated Ca2+ release was nearly abolished (reduced
90%) while caffeine-induced Ca2+ release was only marginally reduced in R4892W-expressing myotubes, indicating that this mutation preferentially disrupts voltage-sensor activation of release. These data demonstrate that CCD mutations in exon 102 disrupt release channel permeation to Ca2+ during EC coupling and that this region represents a primary molecular locus for EC uncoupling in CCD.
Key Words: excitation-contraction coupling • skeletal muscle • calcium channel • muscle disease
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Xu, Y. Wang, N. Yamaguchi, D. A. Pasek, and G. Meissner Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies J. Biol. Chem., March 7, 2008; 283(10): 6321 - 6329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Schug, P. C. A. da Fonseca, C. D. Bhanumathy, L. Wagner II, X. Zhang, B. Bailey, E. P. Morris, D. I. Yule, and S. K. Joseph Molecular Characterization of the Inositol 1,4,5-Trisphosphate Receptor Pore-forming Segment J. Biol. Chem., February 1, 2008; 283(5): 2939 - 2948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Zvaritch, F. Depreux, N. Kraeva, R. E. Loy, S. A. Goonasekera, S. Boncompagni, A. Kraev, A. O. Gramolini, R. T. Dirksen, C. Franzini-Armstrong, et al. An Ryr1I4895T mutation abolishes Ca2+ release channel function and delays development in homozygous offspring of a mutant mouse line PNAS, November 20, 2007; 104(47): 18537 - 18542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Goonasekera, N. A. Beard, L. Groom, T. Kimura, A. D. Lyfenko, A. Rosenfeld, I. Marty, A. F. Dulhunty, and R. T. Dirksen Triadin Binding to the C-Terminal Luminal Loop of the Ryanodine Receptor is Important for Skeletal Muscle Excitation Contraction Coupling J. Gen. Physiol., September 24, 2007; 130(4): 365 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhou, N. Yamaguchi, L. Xu, Y. Wang, C. Sewry, H. Jungbluth, F. Zorzato, E. Bertini, F. Muntoni, G. Meissner, et al. Characterization of recessive RYR1 mutations in core myopathies Hum. Mol. Genet., September 15, 2006; 15(18): 2791 - 2803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wu, M C. A. Ibarra, M. C. V. Malicdan, K. Murayama, Y. Ichihara, H. Kikuchi, I. Nonaka, S. Noguchi, Y. K. Hayashi, and I. Nishino Central core disease is due to RYR1 mutations in more than 90% of patients Brain, June 1, 2006; 129(6): 1470 - 1480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kobayashi, M. L. Bannister, J. P. Gangopadhyay, T. Hamada, J. Parness, and N. Ikemoto Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor J. Biol. Chem., February 25, 2005; 280(8): 6580 - 6587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ducreux, F. Zorzato, C. Muller, C. Sewry, F. Muntoni, R. Quinlivan, G. Restagno, T. Girard, and S. Treves Effect of Ryanodine Receptor Mutations on Interleukin-6 Release and Intracellular Calcium Homeostasis in Human Myotubes from Malignant Hyperthermia-susceptible Individuals and Patients Affected by Central Core Disease J. Biol. Chem., October 15, 2004; 279(42): 43838 - 43846. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Shepherd, F Ellis, J Halsall, P Hopkins, and R Robinson RYR1 mutations in UK central core disease patients: more than just the C-terminal transmembrane region of the RYR1 gene J. Med. Genet., March 1, 2004; 41(3): e33 - 33. [Full Text] [PDF]
|
|
|
|
|
|
C. F. Perez, S. Mukherjee, and P. D. Allen Amino Acids 1-1,680 of Ryanodine Receptor Type 1 Hold Critical Determinants of Skeletal Type for Excitation-Contraction Coupling: ROLE OF DIVERGENCE DOMAIN D2 J. Biol. Chem., October 10, 2003; 278(41): 39644 - 39652. [Abstract] [Full Text] [PDF]
|
|
|
|
