The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

Su, Tsung‐Ping; Tp, Su; Nakamura, Yoki; Tsai, Shang-Yi

doi:10.1016/j.tips.2016.01.003

Cited by 260 publications

(275 citation statements)

References 140 publications

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“…3f). Although σ1 is an inter-organelle signaling modulator that exerts several distinct functions (e.g., ER lipid metabolisms/transports [60], and indirectly regulating the transcription of genes [4]), these data Right: Sample traces. In (a), one-way ANOVA, ****p < 0.0001.…”

Section: Cocaine Decreases Nacsh Neuronal Intrinsic Excitability In Dmentioning

confidence: 99%

“…Previous studies suggest that activation of the sigma-1 receptor (σ1), an endoplasmic reticulum (ER) chaperone [3] that regulates a variety of proteins through physical protein-protein interactions [4], contributes to addiction processes [5,6]. Consistent with this role, σ1 regulates both DA receptors signaling (DARs) via protein-protein interactions [7,8] and DA release in the striatum [9].…”

Section: Introductionmentioning

confidence: 99%

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Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens

et al. 2018

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Drug-induced enhanced dopamine (DA) signaling in the brain is a canonical mechanism that initiates addiction processes. However, indirect evidence suggests that cocaine also triggers non-canonical, DA-independent, mechanisms that contribute to behavioral responses to cocaine, including psychomotor sensitization and cocaine self-administration. Identifying these mechanisms and determining how they are initiated is fundamental to further our understanding of addiction processes. Using physiologically relevant in vitro tractable models, we found that cocaine-induced hypoactivity of nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs), one hallmark of cocaine addiction, is independent of DA signaling. Combining brain slice studies and site-directed mutagenesis in HEK293T cells, we found that cocaine binding to intracellular sigma-1 receptor (σ1) initiates this mechanism. Subsequently, σ1 binds to Kv1.2 potassium channels, followed by accumulation of Kv1.2 in the plasma membrane, thereby depressing NAcSh MSNs firing. This mechanism is specific to D1 receptor-expressing MSNs. Our study uncovers a mechanism for cocaine that bypasses DA signaling and leads to addiction-relevant neuroadaptations, thereby providing combinatorial strategies for treating stimulant abuse.

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Section: Cocaine Decreases Nacsh Neuronal Intrinsic Excitability In Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens

et al. 2018

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“…Identification of the structural elements and amino acids involved in the large number of reported protein-protein interactions (reviewed in [1]) is required to understand the specificity of S1R signaling. It is possible that the interface for protein-protein interactions is only accessible in the monomeric form [32,62,63], however, the surface-exposed helices A and B are attractive potential sites of interaction based on the trimeric structures.…”

Section: Where Is the Interaction Site For Protein-proteinmentioning

confidence: 99%

“…Despite its small size S1R acts to regulate the activity of a large number of cellular proteins and is itself regulated by small molecule binding [1]. The reported protein interaction partners include ion channels (both ligand and voltage gated), GPCRs, transcription factors and the endoplasmic reticulum (ER) chaperone protein BiP [2].…”

Section: Introductionmentioning

confidence: 99%

A Review of the Human Sigma-1 Receptor Structure

Ossa

Schnell

Roldan

2017

Advances in Experimental Medicine and Biology

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The Sigma-1 Receptor (S1R) is a small, ligand-regulated integral membrane protein involved in cell homeostasis and the cellular stress response. The receptor has a multitude of protein and small molecule interaction partners with therapeutic potential. Newly reported structures of the human S1R in ligand-bound states provides essential insights into small molecule binding in the context of the overall protein structure. The structure also raises many interesting questions and provides an excellent starting point for understanding the molecular tricks employed by this small membrane receptor to modulate a large number of signaling events. Here, we review insights from the structures of ligand-bound S1R in the context of previous biochemical studies and propose, from a structural viewpoint, a set of important future directions.

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“…The sigma-1 receptor acts as a ligand-operated chaperone, which modifies the function of several receptors and channels important in neurotransmission (2), and has been the focus of intense preclinical research as a new pharmacological target for pain treatment (3,4). The role of sigma-1 receptors in neuropathic pain has been extensively studied, and it has been widely reported that sigma-1 inhibition decreases central sensitization (3), which plays a key role in this type of pain (5).…”

mentioning

confidence: 99%

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

Tejada

Montilla-García

Cronin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sigma-1 antagonism potentiates the antinociceptive effects of opioid drugs, so sigma-1 receptors constitute a biological brake to opioid drug-induced analgesia. The pathophysiological role of this process is unknown. We aimed to investigate whether sigma-1 antagonism reduces inflammatory pain through the disinhibition of the endogenous opioidergic system in mice. The selective sigma-1 antagonists BD-1063 and S1RA abolished mechanical and thermal hyperalgesia in mice with carrageenan-induced acute (3 h) inflammation. Sigma-1-mediated antihyperalgesia was reversed by the opioid antagonists naloxone and naloxone methiodide (a peripherally restricted naloxone analog) and by local administration at the inflamed site of monoclonal antibody 3-E7, which recognizes the pan-opioid sequence TyrGly-Gly-Phe at the N terminus of most endogenous opioid peptides (EOPs). Neutrophils expressed pro-opiomelanocortin, the precursor of β-endorphin (a known EOP), and constituted the majority of the acute immune infiltrate. β-endorphin levels increased in the inflamed paw, and this increase and the antihyperalgesic effects of sigma-1 antagonism were abolished by reducing the neutrophil load with in vivo administration of an anti-Ly6G antibody. The opioid-dependent sigma-1 antihyperalgesic effects were preserved 5 d after carrageenan administration, where macrophages/monocytes were found to express pro-opiomelanocortin and to now constitute the majority of the immune infiltrate. These results suggest that immune cells harboring EOPs are needed for the antihyperalgesic effects of sigma-1 antagonism during inflammation. In conclusion, sigma-1 receptors curtail immune-driven peripheral opioid analgesia, and sigma-1 antagonism produces local opioid analgesia by enhancing the action of EOPs of immune origin, maximizing the analgesic potential of immune cells that naturally accumulate in painful inflamed areas.sigma-1 receptors | inflammatory pain | endogenous opioid peptides | immune cells

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The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

Cited by 260 publications

References 140 publications

Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens

Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens

A Review of the Human Sigma-1 Receptor Structure

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice

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