The cardiac α1C subunit can support excitation-triggered Ca2+ entry in dysgenic and dyspedic myotubes

Abstract

Depolarization-induced entry of divalent ions into skeletal muscle has been attributed to a process termed Excitation-Coupled Ca2+ Entry (ECCE), which is hypothesized to require the interaction of the ryanodine receptor (RyR1), the L-type Ca2+ channel (DHPR) and another unidentified cation channel. Thus, ECCE is absent in myotubes lacking either the DHPR (dysgenic) or RyR1 (dyspedic). Furthermore, ECCE, as measured by Mn2+ quench of Fura-2, is reconstituted by expression of a mutant DHPR α1S subunit (SkEIIIK) thought to be impermeable to divalent cations. Previously, we showed that the bulk of depolarization-induced Ca2+ entry could be explained by the skeletal L-type current. Accordingly, one would predict that any Ca2+ current similar to the endogenous current would restore such entry and that this entry would not require coupling to either the DHPR or RyR1. Here, we show that expression of the cardiac α1C subunit in either dysgenic or dyspedic myotubes does result in Ca2+ entry similar to that ascribed to ECCE. We also demonstrate that, when potentiated by strong depolarization and Bay K 8644, SkEIIIK supports entry of Mn2+. These results strongly support the idea that the L-type channel is the major route of Ca2+ entry in response to repetitive or prolonged depolarization of skeletal muscle.