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

The multisubunit (alpha(1S), alpha(2)/delta, beta 1(1), and gamma) skeletal muscle dihydropyridine receptor transduces transverse tubule membrane depolarization into release of Ca2+ from the sarcoplasmic reticulum, and also acts as an L-type Ca2+ channel, The cuts subunit contains the voltage sensor and channel pore, the kinetics of which are modified by the other subunits. To determine the role of the beta(1) subunit in channel activity and excitation-contraction coupling we have used gene targeting to inactivate the beta(1) gene, beta(1)-null mice die at birth from asphyxia, Electrical stimulation of beta(1)-null muscle fails to induce twitches, however, contractures are induced by caffeine. In isolated beta(1)-null myotubes, action potentials are normal, but fail to elicit a Ca2+ transient. L-type Ca2+ current is decreased 10- to 20-fold in the beta(1)-null cells compared with littermate controls. Immunohistochemistry of cultured myotubes shows that not only is the beta(1) subunit absent, but the amount of alpha(1S) in the membrane also is undetectable, In contrast, the beta(1) subunit is localized appropriately in dysgenic, mdg/mdg, (alpha(1S)-null) cells, Therefore, the beta(1) subunit may not only play an important role in the transport/insertion of the alpha(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.