| First Author | Tadić V | Year | 2017 |
| Journal | Neuroscience | Volume | 359 |
| Pages | 105-118 | PubMed ID | 28723387 |
| Mgi Jnum | J:249774 | Mgi Id | MGI:6092865 |
| Doi | 10.1016/j.neuroscience.2017.07.012 | Citation | Tadic V, et al. (2017) Sigma 1 receptor activation modifies intracellular calcium exchange in the G93A(hSOD1) ALS model. Neuroscience 359:105-118 |
| abstractText | 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) IP3R-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. |
