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Review
. 2021 Sep 30:15:685201.
doi: 10.3389/fncel.2021.685201. eCollection 2021.

Sigma-1 Receptor: A Potential Therapeutic Target for Traumatic Brain Injury

Mingming Shi  1   2   3 , Fanglian Chen  2   3 , Zhijuan Chen  1 , Weidong Yang  1 , Shuyuan Yue  1 , Jianning Zhang  1   2   3 , Xin Chen  1   2   3
Affiliations
Review

Sigma-1 Receptor: A Potential Therapeutic Target for Traumatic Brain Injury

Mingming Shi et al. Front Cell Neurosci. .

Abstract

The sigma-1 receptor (Sig-1R) is a chaperone receptor that primarily resides at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and acts as a dynamic pluripotent modulator regulating cellular pathophysiological processes. Multiple pharmacological studies have confirmed the beneficial effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity modulation, reactive oxygen species (ROS) clearance, and the structural and functional stability of the ER, mitochondria, and MAM. The Sig-1R is expressed broadly in cells of the central nervous system (CNS) and has been reported to be involved in various neurological disorders. Traumatic brain injury (TBI)-induced secondary injury involves complex and interrelated pathophysiological processes such as cellular apoptosis, glutamate excitotoxicity, inflammatory responses, endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction. Thus, given the pluripotent modulation of the Sig-1R in diverse neurological disorders, we hypothesized that the Sig-1R may affect a series of pathophysiology after TBI. This review summarizes the current knowledge of the Sig-1R, its mechanistic role in various pathophysiological processes of multiple CNS diseases, and its potential therapeutic role in TBI.

Keywords: apoptosis; calcium homeostasis; endoplasmic reticulum stress; excitotoxicity; inflammatory responses; sigma-1 receptor; traumatic brain injury.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The role of sigma-1 receptor in regulating the unfolded protein response signaling. Upon the endoplasmic reticulum (ER) stress, three types of sensors of ER stress: protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α) and activating transcription factor 6 (ATF6) are evoked and triggers a series of downstream signaling pathways that associated various pathophysiological processes including protein folding, lipid metabolism, energy control, differentiation, inflammation and apoptosis. Upon the ER stress or agonist stimulation, sigma-1 receptor (Sig-1R) dissociates from binding immunoglobulin protein (BiP) and immediately participates in regulating the unfolded protein response (UPR)-dependent signaling pathways.
FIGURE 2
FIGURE 2
Molecular mechanisms of sigma-1 receptor in modulation of mitochondrial function and intracellular calcium homeostasis. Upon the ER stress or agonist stimulation, sigma-1 receptor (Sig-1R) dissociates from binding immunoglobulin protein (BiP) and binds to type 3 inositol 1,4,5-trisphosphate receptor (IP3R3), mainly resides at the mitochondria-associated membranes (MAMs). IP3R3s forms a tripartite complex with voltage-dependent anion-selective channel (VDAC) and glucose-regulated protein 75 (GRP75) to connect the ER and the mitochondria. Sig-1R activation facilitates calcium transfer from endoplasmic reticulum (ER) to mitochondria through IP3R3-GRP75-VDAC1 channel. Excessive ROS production promotes mitochondrial permeability transition pore (MPTP) opening, leading to release of cytochrome c from mitochondria to cytosol. Sig-1R may directly form a complex with IP3R, Bcl-2 and Ras-related C3 botulinum toxin substrate 1 (Rac1). Furthermore, Sig-1R can translocate from MAMs to plasma membrane where it directly or indirectly modulates intracellular calcium homeostasis by regulating activities of various plasma membrane elements including N-methyl-D-aspartate receptors (NMDARs), voltage-gated calcium channels (VGCCs), acid-sensing ion channel a (ASIC1a) and stromal interaction molecules 1 (STIM1)/Orai1 complex.
FIGURE 3
FIGURE 3
Sigma-1 receptor determines cell fate by modulation extrasynaptic NMDARs and synaptic NMDARs activities. The subunit GluN2A and GluN2B, respectively, are mainly existed on synaptic and extrasynaptic regions. Both synaptic NMDARs and extrasynaptic NMDARs contribute to calcium transients which trigger a series of nuclear calcium-dependent signaling pathways. They lead to totally opposing biochemical processes and cellular consequences, in which activation of synaptic NMDARs promote cell survival by upregulation of the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (Akt), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), whereas excessive activation of extrasynaptic NMDARs lead to cell death by contribution to CREB shut-off, inactivation Akt and ERK1/2, and activation of pro-death transcription factor forkhead box protein O (FOXO). Agonism of sigma-1 receptor not only promotes the synaptic NMDARs activities, but also inhibits extrasynaptic NMDARs activities.
FIGURE 4
FIGURE 4
Sigma-1 receptor acts as a pluripotent modulator in pathophysiology. The figure indicates a summary of the mechanism in main pathophysiological processes in which sigma-1 receptor (Sig-1R) plays a key role. Numerous pharmacological studies have confirmed the positive effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity, ER stress, mitochondrial function. More experiments and further investigations are urgently needed to advance our understanding of Sig-1R and its specific role in traumatic brain injury.
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