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)/delta-2, beta1, and gamma1 L-type Ca(2+) channel or dihydropyridine receptor functions as a voltage sensor for excitation contraction coupling and is responsible for the L-type Ca(2+) current. The gamma1 subunit, which is tightly associated with this Ca(2+) channel, is a membrane-spanning protein exclusively expressed in skeletal muscle. Previously, heterologous expression studies revealed that gamma1 might modulate Ca(2+) currents expressed by the pore subunit found in heart, alpha(1C), shifting steady state inactivation, and increasing current amplitude. To determine the role of gamma1 assembled with the skeletal subunit composition in vivo, we used gene targeting to establish a mouse model, in which gamma1 expression is eliminated. Comparing litter-matched mice with control mice, we found that, in contrast to heterologous expression studies, the loss of gamma1 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 gamma1-deficient myotubes and, correspondingly, steady state inactivation of I(Ca) was shifted to more positive membrane potentials. These results indicate that gamma1 decreases the amount of Ca(2+) entry during stimulation of skeletal muscle.
Freise
D
D
Institut für Pharmakologie und Toxikologie, Universität des Saarlandes, D-66421 Homburg, Germany.
Held
B
B
Wissenbach
U
U
Pfeifer
A
A
Trost
C
C
Himmerkus
N
N
Schweig
U
U
Freichel
M
M
Biel
M
M
Hofmann
F
F
Hoth
M
M
Flockerzi
V
V
D000818:Animals; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D015640:Ion Channel Gating; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout
D020746:Calcium Channels, L-Type; D017931:DNA Primers