The sigma receptor (σR) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IPRs). The σR is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer's disease (AD) models in vitro and in vivo. σR effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σR ligands in mouse mitochondria preparations on reactive oxygen species (ROS) production, mitochondrial respiration, and complex activities, in physiological condition and after direct application of amyloid Aβ peptide. σR agonists (2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (PRE-084), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (ANAVEX1-41, AN1-41), (S)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one (ANAVEX3-71, AN3-71), dehydroepiandrosterone-3 sulfate (DHEA), donepezil) increased mitochondrial ROS in a σR antagonist-sensitive manner but decreased Aβ-induced increase in ROS. σR ligands (agonists or antagonists) did not impact respiration but attenuated Aβ-induced alteration. σR agonists (PRE-084, AN1-41, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, AN2-73), AN3-71) increased complex I activity, in a Ca-dependent and σR antagonist-sensitive manner. σR ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the σR-induced increase in ROS since ligands failed to affect other sources of ROS accumulation in mitochondria and homogenates, namely NADPH oxidase (NOX) and superoxide dismutase (SOD) activities. Furthermore, Aβ significantly decreased the activity of complexes I and IV and σR agonists attenuated the Aβ-induced complex I and IV dysfunctions. σR activity in mitochondria therefore results in a Ying-Yang effect, by triggering moderate ROS increase acting as a physiological signal and promoting a marked anti-oxidant effect in pathological (Aβ) conditions.

BackgroundSmall Rho-GTPases are critical mediators of neuronal plasticity and are involved in the pathogenesis of several psychiatric and neurological disorders. Rac-GTPase forms a multiprotein complex with upstream and downstream regulators that are essential for the spatiotemporal transmission of Rac signaling. The sigma-1 receptor (Sig1R) is a ligand-regulated membrane protein chaperone, and multiprotein complex assembly is essential to sigma-receptor function.ResultsUsing immunoprecipitation techniques, we have shown that in mitochondrial membranes Sig1R could directly interact with Rac1. Besides Rac1, the Sig1R forms complexes with inositol 1,4,5-trisphosphate receptor and Bcl2, suggesting that mitochondrial associated membranes (MAM) are involved in this macromolecular complex formation. Assembly of this complex is ligand-specific and depends on the presence of sigma agonist/antagonist, as well as on the presence of GTP/GDP. Treatment of mitochondrial membranes with (+)-pentazocine leads to the (+)-pentazocine-sensitive phosphorylation of Bad and the pentazocine-sensitive NADPH-dependent production of ROS.ConclusionWe suggest that Sig1R through Rac1 signaling induces mild oxidative stress that possibly is involved in the regulation of neuroplasticity, as well as in the prevention of apoptosis and autophagy.

The sigma-1 (σ) receptor has been associated with regulation of intracellular Ca homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ receptor agonists can induce cytoprotective responses. These protective responses comprise various complementary pathways that appear to be differentially engaged according to pathological mechanism. Recent studies have highlighted the efficacy of drugs that act through the σ receptor to mitigate symptoms associated with neurodegenerative disorders with distinct mechanisms of pathogenesis. Here, we will review genetic and pharmacological evidence of σ receptor engagement in learning and memory disorders, cognitive impairment, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease.

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The present chapter will review the role of σ receptor in learning and memory and neuroprotection , against Alzheimer's type dementia. σ Receptor agonists have been tested in a variety of pharmacological and pathological models of learning impairments in rodents these last past 20 years. Their anti-amnesic effects have been explained by the wide-range modulatory role of σ receptors on Ca mobilizations, neurotransmitter responses, and particularly glutamate and acetylcholine systems, and neurotrophic factors. Recent observations from genetic and pharmacological studies have shown that σ receptor can also be targeted in neurodegenerative diseases, and particularly Alzheimer's disease . Several compounds, acting partly through the σ receptor, have showed effective neuroprotection in transgenic mouse models of Alzheimer's disease . We will review the data and discuss the possible mechanisms of action, particularly focusing on oxidative stress and mitochondrial integrity, trophic factors and a novel hypothesis suggesting a functional interaction between the σ receptor and α nicotinic acetylcholine receptor. Finally, we will discuss the pharmacological peculiarities of non-selective σ receptor ligands, now developed as neuroprotectants in Alzheimer's disease , and positive modulators, recently described and that showed efficacy against learning and memory deficits.

Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER) chaperones implicated in neuropathic pain. Here we examine if the Sig-1R may relate to neuropathic pain at the level of dorsal root ganglia (DRG). We focus on the neuronal excitability of DRG in a “spare nerve injury” (SNI) model of neuropathic pain in rats and find that Sig-1Rs likely contribute to the genesis of DRG neuronal excitability by decreasing the protein level of voltage-gated Cav2.2 as a translational inhibitor of mRNA. Specifically, during SNI, Sig-1Rs translocate from ER to the nuclear envelope via a trafficking protein Sec61β. At the nucleus, the Sig-1R interacts with cFos and binds to the promoter of 4E-BP1, leading to an upregulation of 4E-BP1 that binds and prevents eIF4E from initiating the mRNA translation for Cav2.2. Interestingly, in Sig-1R knockout HEK cells, Cav2.2 is upregulated. In accordance with those findings, we find that intra-DRG injection of Sig-1R agonist (+)pentazocine increases frequency of action potentials via regulation of voltage-gated Ca2+ channels. Conversely, intra-DRG injection of Sig-1R antagonist BD1047 attenuates neuropathic pain. Hence, we discover that the Sig-1R chaperone causes neuropathic pain indirectly as a translational inhibitor.

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Nerve injury causes abnormal hyperactivity of primary sensory nerves and causes changes in the expression of pro‐ and antinociceptive genes in the DRG. The ER chaperone sigma‐1 receptor (Sig‐1R) was demonstrated to play a role in neuropathic pain and is known to exist in the dorsal root ganglia (DRG), notably, at the nuclear envelope. According to the published data, in Spared Nerve Injury (SNI) model of neuropathic pain, Sig‐1R knockout mice did not develop cold allodynia and showed significantly less mechanical allodynia. However, the molecular mechanisms whereby Sig‐1Rs modulate neuropathic pain at the DRG are largely unknown. Recently, it was shown that the inhibition of histone methyltransferase at the DRG attenuates the neuropathic pain by correcting the dysfunctional potassium channels. Inasmuch as Sig‐1Rs exist at the nuclear envelope, we hypothesized that Sig‐1Rs may participate in the regulation of epigenetic modifications related to neuropathic pain. Immunoblotting of extracted histones from Sig‐1R knockout DRGs, when compared to wild type DRGs, showed a decrease in the level of H3K9me2, whereas total H3 methylation/acetylation, H3K9ac, H3K9me3, H3K27me3 and H3K4me3 histone marks were unchanged. However, the protein level or mRNA expression of euchromatic histone‐lysine N‐methyltransferase‐2 (G9a) which is an enzyme responsible for H3K9me2 modification was not altered in wild type and Sig‐1R knockout mice. Those results suggest that the Sig‐1R plays a role on the maintenance of the level of H3K9me2 downstream of the G9a. It is known that H3K9me2 preferentially marks chromatin at the nuclear periphery that interestingly is where Sig‐1Rs are located. Thus, we performed peptide pulldown experiments using unmodified and modified histone peptides to pull down Sig‐1Rs and found that indeed the H3K9me2 peptide can bind the Sig‐1R. When taken together, those results suggest that the Sig‐1R relates to the maintenance of the H3K9me2 level in the DRG and that the Sig‐1R may affect neuropathic pain by regulating the level of potassium channels by the epigenetic modification on histone 3. Support or Funding Information IRP/NIDA/NIH