Knocking Out Sigma-1 Receptors Reveals Diverse Health Problems.

Sigma-1 receptor (Sig-1R) is a protein present in several organs such as brain, lung, and heart. In a cell, Sig-1R is mainly located across the membranes of the endoplasmic reticulum and more specifically at the mitochondria-associated membranes. Despite numerous studies showing that Sig-1R could be targeted to rescue several cellular mechanisms in different pathological conditions, less is known about its fundamental relevance. In this review, we report results from various studies and focus on the importance of Sig-1R in physiological conditions by comparing Sig-1R KO mice to wild-type mice in order to investigate the fundamental functions of Sig-1R. We note that the Sig-1R deletion induces cognitive, psychiatric, and motor dysfunctions, but also alters metabolism of heart. Finally, taken together, observations from different experiments demonstrate that those dysfunctions are correlated to poor regulation of ER and mitochondria metabolism altered by stress, which could occur with aging.

Genomic Action of Sigma-1 Receptor Chaperone Relates to Neuropathic Pain.

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 Sec61ß. 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.

Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition but Protect Against Pathological Oxidative Stress.

The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca2+ exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IP3Rs). The σ1R 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. σ1R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σ1R 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 Aß1-42 peptide. σ1R 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 σ1R antagonist-sensitive manner but decreased Aß1-42-induced increase in ROS. σ1R ligands (agonists or antagonists) did not impact respiration but attenuated Aß1-42-induced alteration. σ1R 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 Ca2+-dependent and σ1R antagonist-sensitive manner. σ1R ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the σ1R-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, Aß1-42 significantly decreased the activity of complexes I and IV and σ1R agonists attenuated the Aß1-42-induced complex I and IV dysfunctions. σ1R 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 (Aß) conditions.

Sigma-1 (σ1) Receptor in Memory and Neurodegenerative Diseases.

The sigma-1 (σ1) receptor has been associated with regulation of intracellular Ca2+ homeostasis, several cellular signaling pathways, and inter-organelle communication, in part through its chaperone activity. In vivo, agonists of the σ1 receptor enhance brain plasticity, with particularly well-described impact on learning and memory. Under pathological conditions, σ1 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 σ1 receptor to mitigate symptoms associated with neurodegenerative disorders with distinct mechanisms of pathogenesis. Here, we will review genetic and pharmacological evidence of σ1 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.

Role of σ1 Receptors in Learning and Memory and Alzheimer's Disease-Type Dementia.

The present chapter will review the role of σ1 receptor in learning and memory and neuroprotection , against Alzheimer's type dementia. σ1 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 σ1 receptors on Ca2+ mobilizations, neurotransmitter responses, and particularly glutamate and acetylcholine systems, and neurotrophic factors. Recent observations from genetic and pharmacological studies have shown that σ1 receptor can also be targeted in neurodegenerative diseases, and particularly Alzheimer's disease . Several compounds, acting partly through the σ1 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 σ1 receptor and α7 nicotinic acetylcholine receptor. Finally, we will discuss the pharmacological peculiarities of non-selective σ1 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 receptor directly interacts with Rac1-GTPase in the brain mitochondria.

BACKGROUND: Small 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. RESULTS: Using 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. CONCLUSION: We 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.