Trends in Neurosciences
Volume 35, Issue 12, December 2012, Pages 762-771
Journal home page for Trends in Neurosciences

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

https://doi.org/10.1016/j.tins.2012.09.007Get rights and content

Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. Sig-1Rs are intracellular chaperones that reside 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 mechanisms 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 aspects of neurological and psychiatric diseases.

Introduction

The Sig-1R is an ER-resident protein that has been implicated in many diseases, ranging from cocaine or alcohol addiction to the most recently reported familial adult or juvenile amyotrophic lateral sclerosis (ALS) 1, 2, 3. The amino acid sequence of the Sig-1R does not resemble that of any other mammalian proteins. So far, no other members have been found in this class of protein except for a short variant of the Sig-1R that has been recently reported [4]. The so-called ‘sigma-2 receptor’ (Sig-2R) was identified by binding assays in which certain ligands showed slightly different affinities from those at the Sig-1R. However, the Sig-2R has not yet been cloned. The Sig-1R contains two transmembrane regions (Box 1).

Sig-1Rs reside at the specialized ER membrane directly apposing mitochondria, the so-called ‘MAM’ 5, 6. At the MAM, Sig-1Rs have been demonstrated to regulate dendritic spine formation and dendrite arborization [7]. Interestingly, the localization of Sig-1Rs is dynamic in nature. Specially, Sig-1Rs have been shown to translocate from the MAM to other areas of the cell 8, 9 where they can interact with a plethora of membrane targets, including voltage-gated ion channels (VGICs), glutamate and GABA ionotropic receptors, the dopamine (DA) D1 receptor (D1R), muscarinic and nicotinic acetylcholine receptors, neurotrophic tyrosine kinase receptor type 2 (TrkB), and intracellular targets, such as kinases (e.g., Src kinase) and inositol triphosphate (IP3) receptors 9, 10. For brevity, this review focuses on the interaction between Sig-1Rs and ion channels and receptors known to be relevant in neuronal excitability or synaptic strength, and analyzes how these interactions reveal the role of Sig-1Rs in neuronal functions and dysfunctions.

Section snippets

Mechanistic considerations

Information transmission within the brain involves complex and subtle variations in neuronal activity. In particular, electrical signals in the brain are constantly modulated and are heavily influenced by excitatory (glutamate) and inhibitory (GABA) inputs. These, in turn, are translated into excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively), which eventually give rise to action potentials (APs). An AP travels from the somato-dendritic compartment along an axon

Voltage-gated Ca2+ channels

Calcium is probably the ion that controls most neuronal functions, both directly and indirectly. For example, calcium channels control the flux of calcium from extracellular to intracellular compartments, and this may regulate neurotransmitter release at the synaptic level. Calcium can also act as a second messenger to trigger specific intracellular signaling pathways. Overall, whereas Na+ and K+ channels are involved in processes requiring fast transduction signal, calcium plays a role in both

Ligand-gated channels: glutamate and GABA ionotropic receptors

The capability of Sig-R ligands to modulate excitatory transmission in the brain is now well established. Although specific antagonists were not yet available, by combining Sig-R agonists and antagonists with electrophysiological recordings, the first studies showed that the Sig-1R has the potential to modulate NMDAR transmission bidirectionally. This phenomenon has been shown in both the CNS and PNS, including the CA3 field of rat dorsal hippocampus 39, 40, 41, cultured neuronal cells from

How does Sig-1R activity affect overall neuronal excitability?

A substantial amount of information on the effects of Sig-1R activation has been reported. However, little is known about how these effects modulate intrinsic and synaptic excitability and, thus, how they affect overall neuronal excitability. Because of the various effects of the Sig-1R on individual channels, this task might be difficult to resolve. For example, inhibition of Na+ currents by the Sig-1R should decrease AP firing, whereas inhibition of K+ currents should, by contrast, increase

Cellular neurobiology of Sig-1Rs

At the MAM, Sig-1Rs reside in the ceramide-enriched microdomains where they appear to bind ceramide [54]. Sig-1Rs at the MAM have also been shown to bind to binding immunoglobulin protein (BiP), another ER chaperone protein that normally prevents the Sig-1R from translocation 8, 20. The exact relation among the binding of the Sig-1R, BiP, and ceramide is unknown at present. As mentioned earlier, Sig-1Rs can regulate dendrite arborization and dendritic spine formation in hippocampal neurons [7].

Concluding remarks

In summary, the Sig-1R, through various means and diverse targets, is capable of affecting each stage of neuronal transmission. This may explain why the Sig-1R is associated with many brain functions and neurological disorders. A clear, region-specific understanding of how Sig-1Rs can regulate neuronal activity through the modulation of VGICs and glutamate and/or GABA transmission will provide information not only on how Sig-1Rs participate in shaping neuronal activity, but also on how its

Acknowledgments

This work is supported by the Intramural Research Program of NIDA, NIH/DHHS.

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