Biological And Biochemical Characterization Of Sigma Rec

National Institute On Drug Abuse

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Abstract

This project delineates biochemical and pharmacological properties of sigma-1 receptors (Sig-1R). Sig-1R are one-transmembrane proteins at the endoplasmic reticulum (ER) that bind neurosteroids and certain antidepressants. Antidepressants have been known to exert their actions via brain-derived neurotrophic factor (BDNF) but the exact molecular mechanism remains unknown. BDNF can reinforce excitatory glutamatergic transmission in cultured cortical neurons via the phospholipase-gamma (PLC-gamma)/inositol 1,4,5-trisphosphate (IP3)/Ca2+ pathway. Therefore, the possible effects of pretreatment with antidepressants on the BDNF signaling through the PLC-gamma)/IP3/Ca2+ pathway was examined first. Furthermore, because the PLC-gamma/IP3/Ca2+ pathway is shown by us to be regulated by Sig-1R, we examined whether the BDNF signaling stimulated by antidepressants is modulated by Sig-1R. We found that the BDNF-stimulated PLC-gamma activation and the ensued increase in intracellular Ca2+ ([Ca2+]i) were potentiated by pretreatment with imipramine or fluvoxamine, so was the BDNF-induced glutamate release. Furthermore, enhancement of the interaction between PLC-gamma and TrkB (receptor for BDNF) after imipramine pretreatment was observed. Interestingly, BD1047, a potent Sig-1R antagonist, blocked the imipramine-dependent potentiation on the BDNF-induced PLC-gamma activation and glutamate release. In contrast, overexpression of Sig-1R per se, without antidepressant pretreatment, enhances BDNF-induced PLC-gamma activation and glutamate release. These results suggest that antidepressant pretreatment selectively enhance the BDNF signaling on the PLC-gamma/IP3/Ca2+ pathway via Sig-1R, and that Sig-1R plays an important role in BDNF signaling leading to glutamate release. Thus, our results suggest that antidepressants may exert their clinical effects by potentiating BDNF signaling via the overexpression of Sig-1R.