Enhanced dihydropyridine receptor channel activity in the presence of ryanodine receptor

Nakai, Junichi
Dirksen, Robert T.
Nguyen, Hanh T.
Pessah, Isaac N.
Beam, Kurt G.
Allen, Paul D.

(Nakai) Department of Medical Chemistry, Kyoto University Faculty of Medicine, Kyoto 606-01, Japan.
(Nakai, Dirksen, Beam) Department of Anatomy and Neurobiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
(Nguyen, Allen) Department of Cardiology, Laboratory of Molecular Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
(Pessah) Department of Molecular Biosciences, University of California-Davis, School of Veterinary Medicine, Davis, California 95616, USA.
(Allen) Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
(Nakai) Present Address: Department of Anatomy and Neurobiology, Colorado State University, Fort Collins, Colorado 80523, USA.
(Allen) To whom correspondence should be addressed.

Nature 380(6569):p 72-75, March 7, 1996.

EXCITATION-CONTRACTION coupling in skeletal muscle involves a voltage sensor in the plasma membrane which, in response to depolarization, causes an intracellular calcium-release channel to open. The skeletal isoform of the ryanodine receptor (RyR-1) functions as the Calcium²+ -release channel and the dihydropyridine receptor (DHPR) functions as the voltage sensor and also as an L-type Calcium²+ channel . Here we examine the possibility that there is a retrograde signal from RyR-1 to the DHPR, using myotubes from mice homozygous for a disrupted RyR-1 gene (dyspedic mice) . As expected, we find that there is no excitation-contraction coupling in dyspedic myotubes, but we also find that they have a roughly 30-fold reduction in L-type Calcium²+ -current density. Injection of dyspedic myotubes with RyR-1 complementary DNA restores excitation-contraction coupling and causes the density of L-type Calcium²+ current to rise towards normal. Despite the differences in Calcium²+ -current magnitude, measurements of charge movement indicate that the density of DHPRs is similar in dyspedic and RyR-1-expressing myotubes. Our results support the possibility of a retrograde signal by which RyR-1 enhances the function of DHPRs as Calcium²+ channels.