Absence of the gamma 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)/d elta-2, beta 1, and gamma 1 L-type Ca2+ channel or dihydropyridine receptor functions as a voltage sensor for excitation contraction coupling and is r esponsible for the L-type Ca2+ current. The gamma 1 subunit, which is tight ly associated with this Ca2+ channel, is a membrane-spanning protein exclus ively expressed in skeletal muscle. Previously, heterologous expression stu dies revealed that gamma 1 might modulate Ca2+ currents expressed by the po re subunit found in heart, alpha(1C), shifting steady state inactivation, a nd increasing current amplitude. To determine the role of gamma 1 assembled with the skeletal subunit composition in vivo, we used gene targeting to e stablish a mouse model, in which gamma 1 expression is eliminated. Comparin g litter-matched mice with control mice, we found that, in contrast to hete rologous expression studies, the loss of gamma 1 significantly increased th e amplitude of peak dihydropyridine-sensitive I-Ca in isolated myotubes. Wh ereas the activation kinetics of the current remained unchanged, inactivati on of the current was slowed in gamma 1-deficient myotubes and, correspondi ngly, steady state inactivation of I-Ca was shifted to more positive membra ne potentials. These results indicate that gamma 1 decreases the amount of Ca2+ entry during stimulation of skeletal muscle.