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Acta Physiologica 2012; Volume 204, Supplement 689
91st Annual Meeting of The German Physiological Society
3/22/2012-3/25/2012
Dresden, Germany
CORRECT JUNCTIONAL TARGETING AND RETROGRADE SIGNALLING TO THE DIHYDROPYRIDINE RECEPTOR (DHPR) BY A TRUNCATED RYANODINE RECEPTOR (RYR1)
Abstract number: P236
Polster1 A., Ohrtman1 J., Beam1 K., Papadopoulos2 *S.
1University of Colorado - Denver, Physiology and Biophysics, Aurora - Denver, United States
2Uniklinik Kln, Vegetative Physiology, Kln, Germany
Stringent control of intracellular Ca2+ release is a crucial regulatory task for cells, considering the plethora of signaling functions and the potential cytotoxic effects of this cation. In skeletal muscle, the primary gatekeeper of sarcoplasmic reticulum (SR) Ca2+ release is the type 1 ryanodine receptor (RyR1). Activation RyR1 will lead to a rapid increase in intracellular [Ca2+] which will initiate contraction via the activation of myofilaments. RyR1 gating is normally under control of the DHPR, who has the function of voltage sensor, coupling membrane depolarisation to SR Ca2+ release (excitation contraction (ec) coupling). DHPRs and RyR1s reside in very close proximity in SR-t-tubular approximations called junctions. Experimental evidence suggests that direct conformational coupling between the cytoplasmic domain of RyR1 and the DHPR underlies functional cooperation of the two channels. To further investigate the DHPR:RyR1 interaction, we designed an expression plasmid encoding a C-terminally truncated RyR1 consisting of the first 4,300 residues (=cytoplasmic domain) but lacking the C-terminal membrane anchor and the pore domain, and labeled the amino terminus with fluorescent protein. Upon expression in dyspedic (=RyR1 k.o.) myotubes, confocal laser scanning microscopy revealed that the construct not only was able to target to the junctions and to colocalize there with the DHPR, it also was functional in terms of retrograde signaling to the voltage sensor, i.e. it dramatically increased DHPR L-type currents. Thus, the RyR1 does not require its channel pore or its membrane anchor for proper junctional targeting and for functional interaction with the DHPR.
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Acta Physiologica 2012; Volume 204, Supplement 689 :P236