title: Neuregulin-1/ErbB4 signaling regulates Kv4.2-mediated transient outward K+ current through the Akt/mTOR pathway.
abstract: Neuregulin-1 (NRG-1) is a member of a family of neurotrophic factors that is required for the differentiation, migration, and development of neurons. NRG-1 signaling is thought to contribute to both neuronal development and the neuropathology of schizophrenia, which is believed to be a neurodevelopmental disorder. However, few studies have investigated the role of NRG-1 on voltage-gated ion channels. In this study, we report that NRG-1 specifically increases the density of transient outward K(+) currents (IA) in rat cerebellar granule neurons (CGNs) in a time-dependent manner without modifying the activation or inactivation properties of IA channels. The increase in IA density is mediated by increased protein expression of Kv4.2, the main α-subunit of the IA channel, most likely by upregulation of translation. The effect of NRG-1 on IA density and Kv4.2 expression was only significant in immature neurons. Mechanistically, both Akt and mammalian target of rapamycin (mTOR) signaling pathways are required for the increased NRG-1-induced IA density and expression of Kv4.2. Moreover, pharmacological blockade of the ErbB4 receptor reduced the effect of NRG-1 on IA density and Kv4.2 induction. Our data reveal, for the first time, that stimulation of ErbB4 signaling by NRG-1 upregulates the expression of K(+) channel proteins via activation of the Akt/mTOR signaling pathway and plays an important role in neuronal development and maturation. NRG1 does not acutely change IA and delayed-rectifier outward (IK) of rat CGNs, suggesting that it may not alter excitability of immature neurons by altering potassium channel property.
authors.affiliation: State Key Laboratory of Medical Neurobiology, School of Life Sciences and Institutes of Brain Science, Fudan University, Shanghai, China.
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Yao
authors.forename: Ji
authors.initials: J
authors.lastname: Sun
authors.forename: Qian-Ru
authors.initials: QR
authors.lastname: Zhao
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Wang
authors.forename: Yan-Ai
authors.initials: YA
authors.lastname: Mei
mesh_terms: D000818:Animals; D002465:Cell Movement; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D008564:Membrane Potentials; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020890:Neuregulin-1; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D011188:Potassium
keywords: Akt/mTOR; CGNs; ErbB4; Ia; Kv4.2; neuregulin