| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Biochemical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
2 Department of Pharmacology and Physiology, University of Rochester Medical Centre, Rochester, NY, USA
3 Department of Physiology, Innsbruck Medical University, Innsbruck, Austria
4 Department of Anaesthesia Research, Brigham and Women's Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: manfred.grabner{at}uibk.ac.at.
Malignant Hyperthermia (MH) is an inherited pharmacogenetic disorder caused by mutations in the skeletal muscle ryanodine receptor (RyR1) and the 
1S-subunit of the dihydropyridine receptor (DHPR). We characterized the effects of an MH mutation in the DHPR cytoplasmic III-IV loop of 1S (R1086H) on DHPR-RyR1 coupling following reconstitution in dysgenic (1S-null) myotubes. Compared to wild-type 1S, caffeine-activated Ca2+ release occurred at ~5-fold lower concentrations in non-expressing and R1086H-expressing myotubes. Although maximal voltage-gated Ca2+ release was similar in 1S- and R1086H-expressing myotubes, the voltage dependence of Ca2+ release was shifted ~5 mV to more negative potentials in R1086H-expressing myotubes. Our results demonstrate that 1S functions as a negative allosteric modulator of release channel activation by caffeine/voltage and that the R1086H MH mutation in the intracellular III-IV linker disrupts this negative regulatory influence. Moreover, a low concentration of caffeine (2mM) caused a similar shift in voltage dependence of Ca2+ release in 1S- and R1086H-expressing myotubes. Compared to 1S-expressing myotubes, maximal L-channel conductance (Gmax) was reduced in R1086H-expressing myotubes (130 ± 10.2 nS/nF and 88 ± 6.8 nS/nF for 1S and R1086H, respectively; p<0.05). The decrease in Gmax did not result from a change in retrograde coupling with RyR1 as the ratio of maximal conductance to charge movement (Gmax/Qmax) was similar in 1S- and R1086H-expressing myotubes and a similar decrease in Gmax was also observed for an analogous mutation engineered into the cardiac L-channel (R1217H). In addition, both R1086H and R1217H DHPRs targeted normally and colocalized with RyR1 in SR-sarcolemmal junctions. These results indicate that the R1086H MH mutation in 1S enhances RyR1 sensitivity to activation by both endogenous (voltage sensor) and exogenous (caffeine) activators.
This article has been cited by other articles:
|
|
 |
|
  I. Sato, S. Wu, M. C. A. Ibarra, Y. K. Hayashi, H. Fujita, M. Tojo, S. J. Oh, I. Nonaka, S. Noguchi, and I. Nishino Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation Neurology, January 8, 2008; 70(2): 114 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yang, E. Esteve, I. N. Pessah, T. F. Molinski, P. D. Allen, and J. R. Lopez Elevated resting [Ca2+]i in myotubes expressing malignant hyperthermia RyR1 cDNAs is partially restored by modulation of passive calcium leak from the SR Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1591 - C1598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou, J. Yi, L. Royer, B. S. Launikonis, A. Gonzalez, J. Garcia, and E. Rios A probable role of dihydropyridine receptors in repression of Ca2+ sparks demonstrated in cultured mammalian muscle Am J Physiol Cell Physiol, February 1, 2006; 290(2): C539 - C553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Litman and H. Rosenberg Malignant Hyperthermia: Update on Susceptibility Testing JAMA, June 15, 2005; 293(23): 2918 - 2924. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
