Dantrolene-Induced Inhibition of Skeletal L-Type Ca2+ Current Requires RyR1 Expression
Figure 6
Potential models for Dantrolene-mediated inhibition of L-type Ca2+ current and excitation-contraction coupling in skeletal muscle. (a) A simplified model illustrating bidirectional coupling between RyR1 and 1.1, the skeletal muscle L-type Ca2+ channel [2]. The red arrow represents orthograde signal transmitted from 1.1 to RyR1 that engages SR Ca2+ release (i.e., EC coupling). The green arrow represents the retrograde communication transmitted from RyR1 to 1.1 that enhances channel and modifies L-type current activation kinetics. Panels B and C show two possible mechanisms by which Dantrolene alters 1.1 function. (b) Binding of Dantrolene to RyR1 causes conformational changes in RyR1 that reduce SR Ca2+ release (represented by small red arrow) and shifts the activation of L-type currents to more depolarizing test potentials by altering retrograde contacts between RyR1 and 1.1 (represented by horizontal green arrow). (c) Alternatively, dantrolene-induced inhibition of SR Ca2+ release (again represented by small red arrow) and alterations in L-type current activation (again represented by horizontal green arrow) may be a consequence of disruption of interactions between RyR1 and 1.1 that are critical for bidirectional communication between the two channels.
