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BIOLOGICAL SCIENCES / BIOPHYSICS
Bidirectional signaling between calcium channels of skeletal muscle requires multiple direct and indirect interactions

David C. Sheridan^*, Hiroaki Takekura, Clara Franzini-Armstrong^,, Kurt G. Beam^*, Paul D. Allen^¶, and Claudio F. Perez^¶,

*University of Colorado Health and Sciences Center, Aurora, CO 80045; National Institute of Fitness and Sports, Kanoya, Kagoshima 891-2393, Japan; University of Pennsylvania, Philadelphia, PA 19104; and ^¶Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115

Contributed by Clara Franzini-Armstrong, October 27, 2006 (received for review June 29, 2006)

We have defined regions of the skeletal muscle ryanodine receptor (RyR1) essential for bidirectional signaling with dihydropyridine receptors (DHPRs) and for the organization of DHPR into tetrad arrays by expressing RyR1–RyR3 chimerae in dyspedic myotubes. RyR1–RyR3 constructs bearing RyR1 residues 1–1681 restored wild-type DHPR tetrad arrays and, in part, skeletal-type excitation–contraction (EC) coupling (orthograde signaling) but failed to enhance DHPR Ca²⁺ currents (retrograde signaling) to WT RyR1 levels. Within this region, the D2 domain (amino acids 1272–1455), although ineffective on its own, dramatically enhanced the formation of tetrads and EC coupling rescue by constructs that otherwise are only partially effective. These findings suggest that the orthograde signal and DHPR tetrad formation require the contributions of numerous RyR regions. Surprisingly, we found that RyR3, although incapable of supporting EC coupling or tetrad formation, restored a significant level of Ca²⁺ current, revealing a functional interaction with the skeletal muscle DHPR. Thus, our data support the hypotheses that (i) the structural/functional link between RyR1 and the skeletal muscle DHPR requires multiple interacting regions, (ii) the D2 domain of RyR1 plays a key role in stabilizing this interaction, and (iii) a form of retrograde signaling from RyR3 to the DHPR occurs in the absence of direct protein–protein interactions.

calcium release | freeze–fracture | myotubes | voltage clamp

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0609473103/DC1.

To whom correspondence may be addressed. E-mail: cperez{at}zeus.bwh.harvard.edu or armstroc{at}mail.med.upenn.edu

© 2006 by The National Academy of Sciences of the USA

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				R. A. Bannister, H. M. Colecraft, and K. G. Beam Rem Inhibits Skeletal Muscle EC Coupling by Reducing the Number of Functional L-Type Ca2+ Channels Biophys. J., April 1, 2008; 94(7): 2631 - 2638. [Abstract] [Full Text] [PDF]

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