Dysfunction of store-operated calcium channel in muscle cells lacking mg29.
The store-operated calcium channel (SOC) located in the plasma membrane (PM) mediates capacitative entry of extracellular calcium after depletion of intracellular calcium stores in the endoplasmic or sarcoplasmic reticulum (ER/SR). An intimate interaction between the PM and the ER/SR is essential for the operation of this calcium signalling pathway. Mitsugumin 29 (MG29) is a synaptophysin-family-related protein located in the junction between the PM and SR of skeletal muscle. Here, we identify SOC in skeletal muscle and characterise its regulation by MG29 and the ryanodine receptor (RyR) located in the SR. Targeted deletion of mg29 alters the junctional membrane structure, causes severe dysfunction of SOC and SR calcium homeostasis and increases the susceptibility of muscle to fatigue stimulation. Severe dysfunction of SOC is also identified in muscle cells lacking both type 1 and type 3 RyRs, indicating that SOC activation requires an intact interaction between the PM and the SR, and is linked to conformational changes of RyRs. Whereas defective SOC seems to be inconsequential to short-term excitation-contraction coupling, the slow cumulative calcium entry through SOC is crucial for long-term calcium homeostasis, such that reduced SOC activity exaggerates muscle fatigue under conditions of intensive exercise.
Pan
Zui
Z
Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway NJ 08854, USA.
Yang
Dongmei
D
Nagaraj
Ramakrishnan Y
RY
Nosek
Thomas A
TA
Nishi
Miyuki
M
Takeshima
Hiroshi
H
Cheng
Heping
H
Ma
Jianjie
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006706:Homeostasis; D051379:Mice; D018763:Muscle Fatigue; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016708:Synaptophysin / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism*
D015220:Calcium Channels; C111842:Mg29 protein, mouse; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D016708:Synaptophysin; D002118:Calcium