title: Sigma-1 receptor enhances neurite elongation of cerebellar granule neurons via TrkB signaling.
abstract: Sigma-1 receptor (Sig-1R) is an integral membrane protein predominantly expressed in the endoplasmic reticulum. Sig-1R demonstrates a high affinity to various synthetic compounds including well-known psychotherapeutic drugs in the central nervous system (CNS). For that, it is considered as an alternative target for psychotherapeutic drugs. On the cellular level, when Sig-1R is activated, it is known to play a role in neuroprotection and neurite elongation. These effects are suggested to be mediated by its ligand-operated molecular chaperone activity, and/or upregulation of various Ca(2+) signaling. In addition, recent studies show that Sig-1R activation induces neurite outgrowth via neurotrophin signaling. Here, we tested the hypothesis that Sig-1R activation promotes neurite elongation through activation of tropomyosin receptor kinase (Trk), a family of neurotrophin receptors. We found that 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE-084), a selective Sig-1R agonist, significantly promoted neurite outgrowth, and K252a, a Trk inhibitor, attenuated Sig-1R-mediated neurite elongation in cerebellar granule neurons (CGNs). Moreover, we revealed that Sig-1R interacts with TrkB, and PRE-084 treatment enhances phosphorylation of Y515, but not Y706. Thus, our results indicate that Sig-1R activation promotes neurite outgrowth in CGNs through Y515 phosphorylation of TrkB.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; JST, CREST, 5, Sanbancho, Chiyoda-ku, Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujita
authors.forename: Kumi
authors.initials: K
authors.lastname: Shibata
authors.forename: Megumi
authors.initials: M
authors.lastname: Mori
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D020813:Receptor, trkB / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000097605:Sigma-1 Receptor
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D009025:Morpholines; D020813:Receptor, trkB; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C049985:staurosporine aglycone