Reciprocal dihydropyridine and ryanodine receptor interactions in skeletal muscle activation

Abstract

Dihydropyridine (DHPR) and ryanodine receptors (RyRs) are central to transduction of transverse (T) tubular membrane depolarisation initiated by surface action potentials into release of sarcoplasmic reticular (SR) Ca2+ in skeletal muscle excitation-contraction coupling. Electronmicroscopic methods demonstrate an orderly positioning of such tubular DHPRs relative to RyRs in the SR at triad junctions where their membranes come into close proximity. Biochemical and genetic studies associated expression of specific, DHPR and RyR, isoforms with the particular excitation-contraction coupling processes and related elementary Ca2+ release events found respectively in skeletal and cardiac muscle. Physiological studies of intramembrane charge movements potentially related to voltage triggering of Ca2+ release demonstrated a particular qγ charging species identifiable with DHPRs through its T-tubular localization, pharmacological properties, and steep voltage-dependence paralleling Ca2+ release. Its nonlinear kinetics implicated highly co-operative conformational events in its transitions in response to voltage change. The effects of DHPR and RyR agonists and antagonists upon this intramembrane charge in turn implicated reciprocal rather than merely unidirectional DHPR-RyR interactions in these complex reactions. Thus, following membrane potential depolarization, an orthograde qγ-DHPR-RyR signaling likely initiates conformational alterations in the RyR with which it makes contact. The latter changes could then retrogradely promote further qγ-DHPR transitions through reciprocal co-operative allosteric interactions between receptors. These would relieve the resting constraints on both further, delayed, nonlinear qγ-DHPR charge transfers and on RyR-mediated Ca2+ release. They would also explain the more rapid charging and recovery qγ transients following larger depolarizations and membrane potential repolarization to the resting level.