Trends in Neurosciences
ReviewThe sigma-1 receptor: roles in neuronal plasticity and disease
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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