![]() ![]() ![]() Here, we will assess the current knowledge yielded by these multidisciplinary methods, and we will also discuss the frustrating limitations of these approaches. Yet, the basic mechanism of DHPR–RYR1 communication remains elusive. Over the last 20-odd years, multidisciplinary approaches have generated a wealth of knowledge regarding how skeletal DHPRs and RYRs interact in skeletal muscle. ![]() Such links are not thought to exist between cardiac DHPRs and RYR2s because the arrangement of DHPRs into tetrads has not been demonstrated in cardiac muscle. Subsequent work, showing that the distance between DHPRs within tetrads is decreased by exposure to concentrations of ryanodine sufficient to lock RYR1 in a non-conducting state, almost unequivocally demonstrates that skeletal DHPRs are linked (directly or indirectly) to RYR1s ( Paolini et al., 2004). Moreover, these tetrads are arranged in register with the four subunits of every other RYR1. Collectively, these ultrastructural studies revealed that intramembranous particles in the plasma membrane, which appear to represent DHPRs, are arranged into groups of four (“tetrads”) in freeze-fracture replicas of plasma membrane–SR junctions. Collectively, these observations suggest that retrograde coupling, like orthograde coupling, is supported by protein–protein contacts linking RYR1 and the DHPR channel complex ( Beam and Horowicz, 2004).Īlthough the functional evidence for conformational coupling described above provides a solid foundation for the notion that protein–protein interactions link the DHPR and RYR1, this idea is most strongly supported by the elegant work of Franzini-Armstrong and colleagues (cf. Moreover, both orthograde and retrograde coupling depend on the integrity of some of the same structural elements of the DHPR α 1S subunit and RYR1. Just as orthograde coupling does not depend upon Ca 2+ movements through the skeletal DHPR, retrograde, RYR1-dependent enhancement of skeletal L-type current does not depend upon Ca 2+ movements via RYR1. In addition to the orthograde signal (i.e., the EC coupling signal) that is transmitted from the skeletal DHPR to RYR1, a retrograde signal was revealed by the observation that L-type currents of dyspedic (RYR1-null) myotubes were substantially smaller than L-type currents of wild-type myotubes, despite similar membrane expression of the DHPR. For this reason, it is thought that transmission of the EC coupling signal from the voltage-sensing S4 regions of the skeletal DHPR to the pore of the skeletal RYR (RYR1) depends on conformational coupling between these two multimeric channels ( Beam and Horowicz, 2004). Furthermore, unlike cardiac-type EC coupling, which requires the influx of extracellular Ca 2+ via the L-type channel, skeletal-type EC coupling does not require such Ca 2+ influx. The skeletal and cardiac DHPRs have several similarities as well as important differences, which is also the case for the skeletal and cardiac RYRs. As in cardiac muscle, EC coupling in skeletal muscle depends on the response of DHPRs to membrane depolarization and on Ca 2+ release from the SR via RYRs. The Ca 2+ influx conducted by the L-type channel gates cardiac RYRs (RYR2), thereby eliciting the Ca 2+ efflux from the SR that activates the contractile filaments and causes contraction of the myocardium. The movement of the voltage sensors is in turn allosterically coupled to opening of the channel pore. In the heart, translocation of the S4 voltage-sensing helices of cardiac L-type Ca 2+ channels (or 1,4-dihydropyridine receptors ) in response to depolarization of the sarcolemma is the initial event in excitation–contraction (EC) coupling. ![]()
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