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

In skeletal muscle the oligomeric alpha(1S), alpha(2)/delta-1 or alpha(2)/delta-2, beta 1, and gamma 1 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 gamma 1 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 gamma 1 might modulate Ca2+ currents expressed by the pore subunit found in heart, alpha(1C), shifting steady state inactivation, and increasing current amplitude. To determine the role of gamma 1 assembled with the skeletal subunit composition in vivo, we used gene targeting to establish a mouse model, in which gamma 1 expression is eliminated. Comparing litter-matched mice with control mice, we found that, in contrast to heterologous expression studies, the loss of gamma 1 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 gamma 1-deficient myotubes and, correspondingly, steady state inactivation of I-Ca was shifted to more positive membrane potentials. These results indicate that gamma 1 decreases the amount of Ca2+ entry during stimulation of skeletal muscle.