title: Absence of the beta subunit (cchb1) of the skeletal muscle dihydropyridine receptor alters expression of the alpha 1 subunit and eliminates excitation-contraction coupling.
abstract: The multisubunit (alpha 1s, alpha 2/delta, beta 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 alpha 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 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.
authors.affiliation: Waisman Center, University of Wisconsin, Madison 53705, USA. gregg@waisman.wisc.edu
authors.forename: R G
authors.initials: RG
authors.lastname: Gregg
authors.forename: A
authors.initials: A
authors.lastname: Messing
authors.forename: C
authors.initials: C
authors.lastname: Strube
authors.forename: M
authors.initials: M
authors.lastname: Beurg
authors.forename: R
authors.initials: R
authors.lastname: Moss
authors.forename: M
authors.initials: M
authors.lastname: Behan
authors.forename: M
authors.initials: M
authors.lastname: Sukhareva
authors.forename: S
authors.initials: S
authors.lastname: Haynes
authors.forename: J A
authors.initials: JA
authors.lastname: Powell
authors.forename: R
authors.initials: R
authors.lastname: Coronado
authors.forename: P A
authors.initials: PA
authors.lastname: Powers
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D020746:Calcium Channels, L-Type; D003001:Cloning, Molecular; D004622:Embryo, Mammalian; D015698:Genomic Library; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000502:physiology*; D009210:Myofibrils / Q000502:physiology / Q000648:ultrastructure; D011994:Recombinant Proteins / Q000096:biosynthesis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D002118:Calcium