Gene/Protein
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Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
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Query: EC:4.1.99.3 (
PRE
)
1,923
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Aberrations in intracellular calcium (Ca
2+
) have been well established within amyotrophic lateral sclerosis (ALS), a severe
motor neuron disease
. Intracellular Ca
2+
concentration is controlled in part through the endoplasmic reticulum (ER) mitochondria Ca
2+
cycle (ERMCC). The ER supplies Ca
2+
to the mitochondria at close contacts between the two organelles, i.e. the mitochondria-associated ER membranes (MAMs). The Sigma 1 receptor (Sig1R) is enriched at MAMs, where it acts as an inter-organelle signaling modulator. However, its impact on intracellular Ca
2+
at the cellular level remains to be thoroughly investigated. Here, we used cultured embryonic mice spinal neurons to investigate the influence of Sig1R activation on intracellular Ca
2+
homeostasis in the presence of G93A
hSOD1
(G93A), an established ALS-causing mutation. Sig1R expression was increased in G93A motor neurons relative to non-transgenic (nontg) controls. Furthermore, we demonstrated significantly reduced bradykinin-sensitive intracellular Ca
2+
stores in G93A spinal neurons, which were normalized by the Sig1R agonist SA4503. Moreover, SA4503 accelerated cytosolic Ca
2+
clearance following a) AMPAR activation by kainate and b) IP
3
R-mediated ER Ca
2+
release following bradykinin stimulation in both genotypes.
PRE
-084 (another Sig1R agonist) did not exert any significant effects on cytosolic Ca
2+
. Both Sig1R expression and functionality were altered by the G93A mutation, indicating the centrality of Sig1R in ALS pathology. Here, we showed that intracellular Ca
2+
shuttling can be manipulated by Sig1R activation, thus demonstrating the value of using the pharmacological manipulation of Sig1R to understand Ca
2+
homeostasis.
...
PMID:Sigma 1 receptor activation modifies intracellular calcium exchange in the G93A
hSOD1
ALS model. 2872 87
