Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1

Abstract

Sigma1 receptors (σ1Rs) are expressed widely; they bind diverse ligands, including psychotropic drugs and steroids, regulate many ion channels, and are implicated in cancer and addiction. It is not known how σ1Rs exert such varied effects. We demonstrate that σ1Rs inhibit store-operated Ca2+ entry (SOCE), a major Ca2+ influx pathway, and reduce the Ca2+ content of the intracellular stores. SOCE was inhibited by expression of σ1R or an agonist of σ1R and enhanced by loss of σ1R or an antagonist. Within the endoplasmic reticulum (ER), σ1R associated with STIM1, the ER Ca2+ sensor that regulates SOCE. This interaction was modulated by σ1R ligands. After depletion of Ca2+ stores, σ1R accompanied STIM1 to ER–plasma membrane (PM) junctions where STIM1 stimulated opening of the Ca2+ channel, Orai1. The association of STIM1 with σ1R slowed the recruitment of STIM1 to ER–PM junctions and reduced binding of STIM1 to PM Orai1. We conclude that σ1R attenuates STIM1 coupling to Orai1 and thereby inhibits SOCE.

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

“…This tonic Ca 2+ signal is synaptotoxic, contributing to MSN spine loss in the YAC128 HD mouse model in vitro and in vivo (Wu et al, 2016). S1R is known to modulate intracellular Ca 2+ signaling (Hayashi and Su, 2007; Srivats et al, 2016). In the next series of experiments we evaluated effects of pridopidine on MSN Ca 2+ homeostasis.…”

“…Given the role of S1R in the regulation of ER Ca 2+ signaling (Hayashi and Su, 2007; Srivats et al, 2016), we evaluated whether 3-PPP and pridopidine stabilize calcium homeostasis in co-cultured YAC128 MSNs. 16–24 hour treatment with pridopidine suppressed DHPG-induced Ca 2+ release in YAC128 MSNs to WT levels.…”

“…Of potential relevance to these findings, knockdown of S1R by RNAi was reported to affect expression levels of the SOC channel subunit Orai1 (Tsai et al, 2012). It has been reported that S1R overexpression or incubation with S1R agonists suppresses SOC in various cell lines (Brailoiu et al, 2016; Srivats et al, 2016). To explain these results it has been proposed that S1R may suppress SOC by binding to STIM1 and obstructing the interaction of STIM1 and Orai1 (Srivats et al, 2016).…”

“…It has been reported that S1R overexpression or incubation with S1R agonists suppresses SOC in various cell lines (Brailoiu et al, 2016; Srivats et al, 2016). To explain these results it has been proposed that S1R may suppress SOC by binding to STIM1 and obstructing the interaction of STIM1 and Orai1 (Srivats et al, 2016). However, in our experiments pridopidine elevated ER Ca 2+ levels in YAC128 MSNs, which would decouple STIMs from SOC channels.…”

Sigma-1 receptor agonist amitriptyline inhibits store-dependent Ca2+ entry in macrophages

“…Полученные данные согласуются с результатами исследований других авторов, которые обнаружили, что амитриптилин подавляет мобилизацию Са 2+ из депо и последующий депозависимый вход Са 2+ , индуцируемые АТФ или ТГ, в клетках лейкоза человека (линия HL-60) [11]. Установлено также, что агонист рецепторов сигма-1 кокаин ингибирует депозависимый вход Са 2+ , вызываемый ТГ в эндотелиальных клетках сосудов мозга крыс [12], а агонист рецепторов сигма-1, (+)-SKF-10047, подавляет мобилизацию Са 2+ из депо и депозависимый вход Са 2+ , вызываемые ТГ в ооцитах китайского хомячка и клетках эмбриональной почки человека (линия HEK 293) [13]. Кроме того, известно, что амитриптилин блокирует потенциалзависимые Са 2+ -каналы L-типа (Cav1.2) в миоцитах желудочка сердца крыс [14,15].…”