There was an attempt to explain the physiological meaning of

There was an attempt to explain the physiological meaning of the balance between the oligomeric and the monomeric forms of the sigma-1 receptor by the hypothesis that oligomerization of the sigma-1 receptor regulates its ligand-mediated functions [57]. Presumably, the sigma-1 receptor ligands can influence the kinetics of the interaction between the receptor and the so-called client proteins (ion channels, and others) by varying the ratio between the oligomeric and the monomeric forms and shifting the balance towards the former.
The role of the sigma-1 receptor in neuropathology Depression is known to be one of the neuropsychological disorders, in which the sigma-1 receptor plays a key role. In this case, there is an observed dysfunction of the ion channel structures modulated by monoaminergic systems, such as the frontal cortex and the hippocampus. Some antidepressants have the properties of the sigma-1 receptor ligands, modulating many neurotransmitter systems, which involves the antidepressant effect associated with the sigma-1 receptor. Indeed, the sigma-1 receptor agonists exhibit a significant antidepressant effect in various models [60]. Currently, there is evidence that these receptors affect mood by enhancing the serotonergic and glutamatergic neuronal functions, as well as due to the neurotrophic actions. The enhanced activation of serotonergic neurons in the dorsal raphe nucleus is an important effect of the sigma-1 receptor agonists. The activation of the serotonergic transmission under the influence of such agonists starts as early as after two days of treatment, while the clinically significant changes induced by the inhibition of serotonin reuptake appear only two or three weeks after the antidepressant administration started. A quick serotonergic effect of the sigma-1 receptor agonists suggests an earlier onset of the antidepressant action compared to traditional antidepressants. Moreover, a combination of the selective sigma-1 receptor agonist pramipexole and the sertraline antidepressant in sub-effective doses exhibits a synergistic antidepressant-like effect in an experimental model of depression [61]. In patients suffering from depression, there is a decrease of NMDA receptors in the prefrontal cortex and hippocampus. An experimental model of depression (olfactory bulbectomy in rats leading to a decrease in the number of NMDA receptors) is accompanied by a behavioral deficit resembling agitation, loss of interest and cognitive dysfunction typical for clinical depression. The sigma-1 receptor agonists improve the behavioral deficit and also increase the expression of NMDA receptors. These findings suggest a link between depression and two types of receptors: NMDA and sigma-1 [20]. Along with the modulating role of the sigma-1 receptors in the glutamatergic and serotonergic transmission associated with depression, they have an additional mechanism of action related to neuroplastic processes. The neurotrophic effect of some antidepressants due to the induction of the neuronal growth factor can be regulated by the sigma-1 receptors [62]. A high binding affinity of fluvoxamine in therapeutic doses for the sigma-1 receptors in the brain indicates that some effects of this antidepressant are connected precisely with the receptors in question. Thus, the analysis of preclinical studies allows to suggest possible additional clinical effects of the antidepressants with the properties of the sigma-1 receptor agonists. Clinicians are focused on such phenomena as the improvement of cognitive abilities, the acceleration of the antidepressant action; the neuroprotective effect [63]. There is also data pointing to the physiological role of the sigma-1 receptor in motor neurons. In particular, it was found that the E102Q mutation in the receptor leads to an autosomal recessive form of juvenile paralysis [64]. Motor neurons of the spinal cord die in the course of this disease. Life expectancy is significantly reduced in mutant mice with the deleted gene of the sigma-1 receptor showing symptoms of paralysis, and the paralysis symptoms occur earlier than in the mice expressing the sigma-1 receptor. This suggests that this receptor inhibits the development of degenerative processes even in mice [65]. The exact role of the sigma-1 receptor has not yet been determined, but different hypotheses have been proposed.