Absence of the γ subunit of the skeletal muscle dihydropyridine receptor increases L-type Ca2+ currents and alters channel inactivation properties

Abstract

In skeletal muscle the oligomeric α(1S), α2/δ-1 or α2/δ-2, β1, and γ1 L-type Ca2+ channel or dihydropyridine receptor functions as a voltage sensor for excitation contraction coupling and is responsible for the L-type Ca2+ current. The γ1 subunit, which is tightly associated with this Ca2+ channel, is a membrane-spanning protein exclusively expressed in skeletal muscle. Previously, heterologous expression studies revealed that γ1 might modulate Ca2+ currents expressed by the pore subunit found in heart, α(1C), shifting steady state inactivation, and increasing current amplitude. To determine the role of γ1 assembled with the skeletal subunit composition in vivo, we used gene targeting to establish a mouse model, in which γ1 expression is eliminated. Comparing litter-matched mice with control mice, we found that, in contrast to heterologous expression studies, the loss of γ1 significantly increased the amplitude of peak dihydropyridine-sensitive I(Ca) in isolated myotubes. Whereas the activation kinetics of the current remained unchanged, inactivation of the current was slowed in γ1-deficient myotubes and, correspondingly, steady state inactivation of I(Ca) was shifted to more positive membrane potentials. These results indicate that γ1 decreases the amount of Ca2+ entry during stimulation of skeletal muscle.