Schematic depicting potential mechanisms for Rem-mediated EC uncoupling. (A) The diagram represents the intact CaV1.1–RYR1 ultrastructure requisite for skeletal-type EC coupling. Four CaV1.1 α1S (red circles)–β1a (white ovals) channel complexes are shown coupled to each subunit of a single RYR1 (gray tetramer) from a transverse-tubular vantage point. For clarity, the β1a subunits are superimposed on the α1S subunits, and the α2δ-1 subunits, γ1 subunits, and other nonessential components of the junction have been omitted. The orientation of β1a within the tetrad follows on previous work (Leuranguer et al., 2006; Sheridan et al., 2012). In the right panels (B and C), we present two potential mechanisms by which Rem (black ovals) may disrupt EC coupling. In B, Rem displaces the CaV1.1 channel complex from RYR1 sufficiently to disrupt the tetradic ultrastructure that is required for CaV1.1–RYR1 communication by interacting with the conserved guanylate kinase–like domain of β1a (Finlin et al., 2006; Béguin et al., 2007) on the periphery of the tetrad (Szpyt et al., 2012). If ultrastructure is preserved in Rem-overexpressing fibers (as depicted in C), the binding of Rem to β1a within the intact CRU would most likely induce conformational rearrangements within β1a that deter transmission of the EC coupling signal from the membrane-bound, voltage-sensing regions of CaV1.1 to RYR1.
