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1 Department of Anesthesia Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Life Science, Kwangju Institute of Science and Technology, Kwangju, Korea, Republic of
2 Department of Anesthesia Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
3 Department of Molecular Bioscience, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
4 Department of Anesthesia Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; CeSI Center for Research on Ageing, Universita degli Studi G. d'Annunzio, Chieti, Italy
5 Department of Life Science, Kwangju Institute of Science and Technology, Kwangju, Korea, Republic of
* To whom correspondence should be addressed. E-mail: Allen{at}zeus.bwh.harvard.edu.
Four RyR1-RyR2 chimeras (R4, R9, R10 and R16) and their respective wild type ryanodine receptors (type 1 and 2; wtRyR1 and wtRyR2) were expressed in dyspedic 1B5 to identify possible negative regulatory modules of the Ca2+ release channel that are under the influence of the dihydropyridine receptor (DHPR). Responses of intact 1B5 myotubes expressing each construct to caffeine in the absence or presence of either La3+ and Cd2+ or the organic DHPR blocker nifedipine were determined by imaging single 1B5 myotubes loaded with fluo-4. The presence of La3+ and Cd2+ or nifedipine in the external medium at concentrations known to block Ca2+ entry through the DHPRs significantly decreased the caffeine EC50 of wtRyR1 (2.80±0.12 to 0.83±0.09 mM; P<0.05). On the other hand, DHPR blockade did not significantly alter the caffeine EC50s of wtRyR2, chimera R10 and R16, while the caffeine EC50s of chimera R4 and R9 were significantly increased (1.27±0.05 to 2.60±0.16 mM, and 1.15±0.03 to 2.11±0.32 mM, respectively; P<0.05). Despite the fact that all the chimeras form fully functional Ca2+ release channels in situ, SR containing R4, R10 and R16 did not possess high-affinity binding of [3H]ryanodine regardless of Ca2+ concentration. These results suggest the presence of an interaction between RyR1 and the DHPR, which is not present in RyR2 that contributes negative control of SR Ca2+ release induced by direct agonists such as caffeine. Although we were unable to define the negative module using RyR1-RyR2 chimeras, they further demonstrated that the RyR is very sensitive to long range allosterism.
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