The sigma-1 receptor: roles in neuronal plasticity and disease

Abstract

Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. The Sig-1R is an intracellular chaperone that resides specifically at the endoplasmic reticulum (ER)-mitochondrion interface referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER-mitochondrion Ca2+ signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanism linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating some aspects of neurological and psychiatric diseases.

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

“…Sig-1Rs have been implicated in many physiological functions (3,10,13,(42)(43)(44)(45)(46)(47). Our results from the present study add an additional function of Sig-1R, in that it regulates gene expression at the NE.…”

The effects of sigma (σ1) receptor‐selective ligands on muscarinic receptor antagonist‐induced cognitive deficits in mice

“…The σ1 receptor is a 25 kDa protein that shares no amino acid sequence homology with any of the known mammalian proteins (Seth et al, 1998;Hayashi and Su, 2005;Kourrich et al, 2012). The σ1 receptor possesses two transmembrane spanning regions.…”

“…In the periphery, σ1 receptors are expressed in the heart, lungs, kidneys, liver and gonads (Vilner et al, 1995;Kitaichi et al, 2000;Hayashi and Su, 2005). This receptor has been identified as an endoplasmic reticulum (ER) resident protein located on the interface of the ER and mitochondria (Hayashi and Su, 2007).The σ1 receptor is a 25 kDa protein that shares no amino acid sequence homology with any of the known mammalian proteins (Seth et al, 1998;Hayashi and Su, 2005;Kourrich et al, 2012). The σ1 receptor possesses two transmembrane spanning regions.…”

“…Recently, Fontanilla and co-workers suggested that the hallucinogen N,N-dimethyltryptamine may be the endogenous ligand (Fontanilla et al, 2009). In addition, the neurosteroids progesterone, pregnonolone sulfate and dehydroepiandrosterone sulfate have appreciable affinity for the σ1 receptor Kourrich et al, 2012).Rather than being a classical receptor signalling unit, σ1 receptors probably act as intracellular modulators of a variety of signal transduction systems. The σ1 receptor has also been postulated to act as a molecular chaperone that regulates cellular survival and synaptogenesis (Hayashi and Su, 2007;Tsai et al, 2009;Fujimoto et al, 2012).…”

“…Ligands selective for σ1 receptors have been reported to exert antidepressant-like, anxiolytic and analgesic actions in preclinical studies (Hayashi et al, 2011). In addition, σ1 receptor occupation has been linked to neurorestorative effects and has been suggested as a novel therapeutic target for the treatment of cognition deficit (Maurice et al, 1994;Urani et al, 1998;Maurice, 2002;Espallergues et al, 2007;Antonini et al, 2011;van Waarde et al, 2011;Kourrich et al, 2012).Our laboratory previously reported on the neuroprotective properties of the σ1 receptor ligand, LS-1-137, which is a novel N-(benzylpiperidin)phenylacetamide that binds to the σ1 receptor with high affinity (Ki value = 3.2 nM) and exhibits 80-fold binding selectivity for the σ1, over the σ2 receptor . LS-1-137 was found to protect HT-22 neuronal cells from glutamate-induced cell death and LS-1-137 was found in vivo to significantly reduce the ischaemic lesion volume in rats using a transient middle cerebral artery occlusion model of stroke (Luedtke et al, 2012).…”