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

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.