CONTRACTIONS OF DYSGENIC SKELETAL-MUSCLE TRIGGERED BY A POTENTIATED, ENDOGENOUS CALCIUM CURRENT

The dihydropyridine (DHP) receptor of normal skeletal muscle is hypothesized to function as the voltage sensor for excitation-contraction (E-C) coupling, and also as the calcium channel underlying a slowly activating, DHP-sensitive current (termed I(Ca-s)). Skeletal muscle from mice with muscular dysgenesis lacks both E-C coupling and I(Ca-s). However, dysgenic skeletal muscle does express a small DHP-sensitive calcium current (termed I(Ca-dys) which is kinetically and pharmacologically distinct from I(Ca-s). We have examined the ability of I(Ca-dys), or the DHP receptor underlying it, to couple depolarization and contraction. Under most conditions I(Ca-dys)) is small (approximately 1 pA/pF) and dysgenic myotubes do not contract in response to sarcolemmal depolarization. However, in the combined presence of the DHP agonist Bay K 8644 (1-mu-M) and elevated external calcium (10 mM), I(Ca-dys) is strongly potentiated and some dysgenic myotubes contract in response to direct electrical stimulation. These contractions are blocked by removing external calcium, by adding 0.5 mM cadmium to the bath, or by replacing Bay K 8644 with the DHP antagonist (+)-PN 200-110. Only myotubes having a density of I(Ca-dys) greater than approximately 4 pA/pF produce detectable contractions, and the strength of contraction is positively correlated with the density of I(Ca-dys). Thus, unlike the contractions of normal myotubes, the contractions of dysgenic myotubes require calcium entry. These results demonstrate that the DHP receptor underlying I(Ca-dys) is unable to function as a "voltage sensor" that directly couples membrane depolarization to calcium release from the sarcoplasmic reticulum.