Saturday, July 22, 2017 12:10:10 AM
Sigma 1 receptor activation modifies intracellular calcium exchange in the G93AhSOD1 ALS model.
Tadic V1, Malci A2, Goldhammer N3, Stubendorff B4, Sengupta S5, Prell T6, Keiner S7, Liu J8, Guenther M9, Frahm C10, Witte OW11, Grosskreutz J12.
Author information
1
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: vedrana.tadic@med.uni-jena.de.
2
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: aysemalci@gmail.com.
3
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: nadinegoldhammer@gmx.de.
4
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: beatrice.stubendorff@med.uni-jena.de.
5
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: saikata.sengupta@med.uni-jena.de.
6
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: tino.prell@med.uni-jena.de.
7
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: silke.keiner@med.uni-jena.de.
8
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: drjingyuliu@hotmail.com.
9
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: madlen.guenter@med.uni-jena.de.
10
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: christiane.frahm@med.uni-jena.de.
11
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: otto.witte@med.uni-jena.de.
12
Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address: julian.grosskreutz@med.uni-jena.de.
Abstract
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 signalling 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.
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George
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