retrograde signal from RyR1 alters DHP receptor inactivation and limits window Ca²⁺ release in muscle fibers of Y522S RyR1 knock-in mice

Malignant hyperthermia (MH) is a life-threatening hypermetabolic condition caused by dysfunctional Ca²⁺ homeostasis in skeletal muscle, which primarily originates from genetic alterations in the Ca²⁺ release channel (ryanodine receptor, RyR1) of the sarcoplasmic reticulum (SR). Owing to its physical...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-03, Vol.106 (11), p.4531-4536
Main Authors: Andronache, Zoita, Hamilton, Susan L, Dirksen, Robert T, Melzer, Werner
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Calcium
Calcium - metabolism
Calcium Channels, L-Type - metabolism
Depolarization
Dihydropyridines
Electric potential
Electrophysiology
Fluorescence
Gene Knock-In Techniques
Genetic mutation
Intracellular Membranes - physiology
Malignant hyperthermia
Malignant Hyperthermia - etiology
Malignant Hyperthermia - genetics
Membrane Potentials
Mice
Mice, Mutant Strains
Muscle fibers
Muscle Fibers, Skeletal - metabolism
Muscle, Skeletal
Mutation, Missense
Receptors
Ryanodine Receptor Calcium Release Channel - genetics
Ryanodine Receptor Calcium Release Channel - metabolism
Signal Transduction - genetics
Skeletal muscle
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Summary:Malignant hyperthermia (MH) is a life-threatening hypermetabolic condition caused by dysfunctional Ca²⁺ homeostasis in skeletal muscle, which primarily originates from genetic alterations in the Ca²⁺ release channel (ryanodine receptor, RyR1) of the sarcoplasmic reticulum (SR). Owing to its physical interaction with the dihydropyridine receptor (DHPR), RyR1 is controlled by the electrical potential across the transverse tubular (TT) membrane. The DHPR exhibits both voltage-dependent activation and inactivation. Here we determined the impact of an MH mutation in RyR1 (Y522S) on these processes in adult muscle fibers isolated from heterozygous RyR1Y⁵²²S-knock-in mice. The voltage dependence of DHPR-triggered Ca²⁺ release flux was left-shifted by [almost equal to]8 mV. As a consequence, the voltage window for steady-state Ca²⁺ release extended to more negative holding potentials in muscle fibers of the RyR1Y⁵²²S-mice. A rise in temperature from 20° to 30 °C caused a further shift to more negative potentials of this window (by [almost equal to]20 mV). The activation of the DHPR-mediated Ca²⁺ current was minimally changed by the mutation. However, surprisingly, the voltage dependence of steady-state inactivation of DHPR-mediated calcium conductance and release were also shifted by [almost equal to]10 mV to more negative potentials, indicating a retrograde action of the RyR1 mutation on DHPR inactivation that limits window Ca²⁺ release. This effect serves as a compensatory response to the lowered voltage threshold for Ca²⁺ release caused by the Y522S mutation and represents a novel mechanism to counteract excessive Ca²⁺ leak and store depletion in MH-susceptible muscle.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0812661106