Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P21817 (
RyR1
)
1,154
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Aim:
We hypothesize that both type-1 ryanodine receptor (
RyR1
) and IP
3
-receptor (IP
3
R) calcium channels are necessary for the mitochondrial Ca
2+
increase caused by membrane depolarization induced by potassium (or by electrical stimulation) of single skeletal muscle fibers; this calcium increase would couple muscle fiber excitation to an increase in metabolic output from mitochondria (excitation-metabolism coupling).
Methods:
Mitochondria matrix and cytoplasmic Ca
2+
levels were evaluated in fibers isolated from
flexor digitorium brevis
muscle using plasmids for the expression of a mitochondrial Ca
2+
sensor (CEPIA3
mt
) or a cytoplasmic Ca
2+
sensor (RCaMP). The role of intracellular Ca
2+
channels was evaluated using both specific pharmacological inhibitors (xestospongin B for IP
3
R and Dantrolene for
RyR1
) and a genetic approach (shIP
3
R1-RFP). O
2
consumption was detected using Seahorse Extracellular
Flux
Analyzer.
Results:
In isolated muscle fibers cell membrane depolarization increased both cytoplasmic and mitochondrial Ca
2+
levels. Mitochondrial Ca
2+
uptake required functional inositol IP
3
R and
RyR1
channels. Inhibition of either channel decreased basal O
2
consumption rate but only
RyR1
inhibition decreased ATP-linked O
2
consumption. Cell membrane depolarization-induced Ca
2+
signals in sub-sarcolemmal mitochondria were accompanied by a reduction in mitochondrial membrane potential; Ca
2+
signals propagated toward intermyofibrillar mitochondria, which displayed increased membrane potential. These results are compatible with slow, Ca
2+
-dependent propagation of mitochondrial membrane potential from the surface toward the center of the fiber.
Conclusion:
Ca
2+
-dependent changes in mitochondrial membrane potential have different kinetics in the surface vs. the center of the fiber; these differences are likely to play a critical role in the control of mitochondrial metabolism, both at rest and after membrane depolarization as part of an "excitation-metabolism" coupling process in skeletal muscle fibers.
...
PMID:Mitochondrial Calcium Increase Induced by RyR1 and IP3R Channel Activation After Membrane Depolarization Regulates Skeletal Muscle Metabolism. 2998 64
