Sigma 1 receptor activation modifies intracellular calcium exchange in the G93AhSOD1 ALS model.
Aberrations in intracellular calcium (Ca2+) have been well established within amyotrophic lateral sclerosis (ALS), a severe motor neuron disease. Intracellular Ca2+ concentration is controlled in part through the endoplasmic reticulum (ER) mitochondria Ca2+ cycle (ERMCC). The ER supplies Ca2+ 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 Ca2+ 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 Ca2+ homeostasis in the presence of G93AhSOD1 (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 Ca2+ stores in G93A spinal neurons, which were normalized by the Sig1R agonist SA4503. Moreover, SA4503 accelerated cytosolic Ca2+ clearance following a) AMPAR activation by kainate and b) IP3R-mediated ER Ca2+ release following bradykinin stimulation in both genotypes. PRE-084 (another Sig1R agonist) did not exert any significant effects on cytosolic Ca2+. Both Sig1R expression and functionality were altered by the G93A mutation, indicating the centrality of Sig1R in ALS pathology. Here, we showed that intracellular Ca2+ shuttling can be manipulated by Sig1R activation, thus demonstrating the value of using the pharmacological manipulation of Sig1R to understand Ca2+ homeostasis.
['Tadić|Vedrana|V|', 'Malci|Ayse|A|', 'Goldhammer|Nadine|N|', 'Stubendorff|Beatrice|B|', 'Sengupta|Saikata|S|', 'Prell|Tino|T|', 'Keiner|Silke|S|', 'Liu|Jingyu|J|', 'Guenther|Madlen|M|', 'Frahm|Christiane|C|', 'Witte|Otto W|OW|', 'Grosskreutz|Julian|J|']
D000690:Amyotrophic Lateral Sclerosis D000818:Animals D002118:Calcium D020013:Calcium Signaling D002478:Cells, Cultured D004195:Disease Models, Animal D006801:Humans D008297:Male D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009046:Motor Neurons D010879:Piperazines D018091:Receptors, AMPA D017480:Receptors, sigma D013116:Spinal Cord D000072105:Superoxide Dismutase-1
calcium ALS ERMCC Sig1R G93A SOD1