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

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Abstract
The multisubunit (α1S, α2/δ, β1, and γ) 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 α1S subunit contains the voltage sensor and channel pore, the kinetics of which are modified by the other subunits. To determine the role of the β1 subunit in channel activity and excitation-contraction coupling we have used gene targeting to inactivate the β1 gene. β1-null mice die at birth from asphyxia. Electrical stimulation of β1-null muscle fails to induce twitches, however, contractures are induced by caffeine. In isolated β1-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 β1-null cells compared with littermate controls. Immunohistochemistry of cultured myotubes shows that not only is the β1 subunit absent, but the amount of α1S in the membrane also is undetectable. In contrast, the β1 subunit is localized appropriately in dysgenic, mdg/mdg, (α1S-null) cells. Therefore, the β1 subunit may not only play an important role in the transport/insertion of the α1S subunit into the membrane, but may be vital for the targeting of the muscle dihydropyridine receptor complex to the transverse tubule/sarcoplasmic reticulum junction.