Absence of the β subunit ( cchb1 ) of the skeletal muscle dihydropyridine receptor alters expression of the α 1 subunit and eliminates excitation-contraction coupling

Abstract

The multisubunit (α 1S , α 2 /δ, β 1 , and γ) skeletal muscle dihydropyridine receptor transduces transverse tubule membrane depolarization into release of Ca 2+ from the sarcoplasmic reticulum, and also acts as an L-type Ca 2+ channel. The α 1S subunit contains the voltage sensor and channel pore, the kinetics of which are modified by the other subunits. To determine the role of the β 1 subunit in channel activity and excitation-contraction coupling we have used gene targeting to inactivate the β 1 gene. β 1 -null mice die at birth from asphyxia. Electrical stimulation of β 1 -null muscle fails to induce twitches, however, contractures are induced by caffeine. In isolated β 1 -null myotubes, action potentials are normal, but fail to elicit a Ca 2+ transient. L-type Ca 2+ current is decreased 10- to 20-fold in the β 1 -null cells compared with littermate controls. Immunohistochemistry of cultured myotubes shows that not only is the β 1 subunit absent, but the amount of α 1S in the membrane also is undetectable. In contrast, the β 1 subunit is localized appropriately in dysgenic, mdg/mdg , (α 1S -null) cells. Therefore, the β 1 subunit may not only play an important role in the transport/insertion of the α 1S subunit into the membrane, but may be vital for the targeting of the muscle dihydropyridine receptor complex to the transverse tubule/sarcoplasmic reticulum junction.