We recently demonstrated that endoplasmic reticulum (ER) stress induces sigma-1 receptor (Sig-1R) expression through the PERK pathway, which is one of the cell''s responses to ER stress. In addition, it has been demonstrated that induction of Sig-1R can repress cell death signaling. Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with a high affinity for Sig-1R. In the present study, we show that treatment of neuroblastoma cells with Flv induces Sig-1R expression by increasing ATF4 translation directly, through its own activation, without involvement of the PERK pathway. The Flv-mediated induction of Sig-1R prevents neuronal cell death resulting from ER stress. Moreover, Flv-induced ER stress resistance reduces the infarct area in mice after focal cerebral ischemia. Thus, Flv, which is used frequently in clinical practice, can alleviate ER stress. This suggests that Flv could be a feasible therapy for cerebral diseases caused by ER stress.Sigma-1 receptor (Sig-1R) is expressed on endoplasmic reticulum (ER) membranes. Several functions have been attributed to Sig-1R, including regulation of ion channels such as Ca2+ and K+ channels, inhibition of Ca2+ influx through the
N-methyl-D-aspartate (NMDA) receptor, modulation of the release of neurotransmitters such as dopamine, regulation of lipid distribution, cell differentiation, and behavioral sensitization to cocaine and other stimulants.
1 Recently, Sig-1R was shown to have neuroprotective activity, and several studies have demonstrated that it acts as a molecular chaperone.
2, 3, 4 Under normal conditions, Sig-1R forms a complex with another molecular chaperone, GRP78/BiP, on the ER membrane. Under ER stress, Sig-1R dissociates from BiP, interacts with IP3 receptors, and stabilizes IP3 receptor structure.
4Numerous studies have examined the role of Sig-1R in the pathogenesis of psychiatric diseases. Postmortem analysis has shown that Sig-1R expression is reduced in the brains of schizophrenia patients.
5 Additionally, Sig-1R knockout mice exhibit symptoms of depression.
6 Given these observations, it is possible that reduction of Sig-1R is a pathogenic factor in disorders such as schizophrenia and depression. Therefore, numerous synthetic compounds that bind to Sig-1R, including antidepressants and antipsychotic drugs, have been examined as therapeutic targets for these disorders.
7 However, the results of clinical testing have not been satisfactory.
8 One possible reason is that the effects of compounds that bind to Sig-1R cannot fully manifest because Sig-1R expression is reduced in the brains of patients with psychiatric diseases. This led us to examine whether compounds capable of inducing Sig-1R expression might be therapeutic in these diseases.When cells encounter ER stress, Sig-1R expression increases in response to activation of the PERK pathway, which is one of the cellular responses to ER stress.
9 In addition, the induction of Sig-1R expression can repress cell death signals that accompany ER stress.
9Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) that is widely used in clinical practice as an antidepressant. Because Flv is a potent Sig-1R agonist that exhibits a stronger affinity for Sig-1R than for other SSRIs,
10 we investigated its effect on Sig-1R expression and on the cellular ER stress responses.
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