The Journal of General Physiology
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Published online 12 August 2002 doi:10.1085/jgp.20028617
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© Rockefeller University Press, 0022-1295/2002/9/337/ $5.00
Journal of General Physiology, Volume 120, Number 3, September 2002 337-347

Calmodulin Binding to the 3614–3643 Region of RyR1 Is Not Essential for Excitation–Contraction Coupling in Skeletal Myotubes

Kristen M.S. O'Connell1, Naohiro Yamaguchi2, Gerhard Meissner2 and Robert T. Dirksen1

1 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
2 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599

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

Calmodulin is a ubiquitous Ca2+ binding protein that modulates the in vitro activity of the skeletal muscle ryanodine receptor (RyR1). Residues 3614–3643 of RyR1 comprise the CaM binding domain and mutations within this region result in a loss of both high-affinity Ca2+-bound calmodulin (CaCaM) and Ca2+-free CaM (apoCaM) binding (L3624D) or only CaCaM binding (W3620A). To investigate the functional role of CaM binding to this region of RyR1 in intact skeletal muscle, we compared the ability of RyR1, L3624D, and W3620A to restore excitation–contraction (EC) coupling after expression in RyR1-deficient (dyspedic) myotubes. W3620A-expressing cells responded normally to 10 mM caffeine and 500 µM 4-chloro-m-cresol (4-cmc). Interestingly, L3624D-expressing cells displayed a bimodal response to caffeine, with a large proportion of cells (~44%) showing a greatly attenuated response to caffeine. However, high and low caffeine-responsive L3624D-expressing myotubes exhibited Ca2+ transients of similar magnitude after activation by 4-cmc (500 µM) and electrical stimulation. Expression of either L3624D or W3620A in dyspedic myotubes restored both L-type Ca2+ currents (retrograde coupling) and voltage-gated SR Ca2+ release (orthograde coupling) to a similar degree as that observed for wild-type RyR1, although L-current density was somewhat larger and activated at more hyperpolarized potentials in W3620A-expressing myotubes. The results indicate that CaM binding to the 3614–3643 region of RyR1 is not essential for voltage sensor activation of RyR1.

Key Words: ryanodine receptor • muscle • calcium channel • caffeine • sarcoplasmic reticulum


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