title: Neuronal activity-dependent STAT3 localization to nucleus is dependent on Tyr-705 and Ser-727 phosphorylation in rat hippocampal neurons.
abstract: Signal transducer and activator of transcription 3 (STAT3) dramatically increases during the first post-natal week, and supports the survival of mature hippocampal neurons. Recently, we reported that chronic elevation of excitability leads to a loss of STAT3 signal, inducing vulnerability in neurons. The loss of STAT3 signal was due to impaired Erk1/2 activation. While overnight elevation of activity attenuated STAT3 signal, brief low-frequency stimuli, which induce long-term depression, have been shown to activate STAT3. Here we investigated how STAT3 responds to depolarization in mature neurons. A brief depolarization results in the transient activation of STAT3: it induces calcium influx through L-type voltage-gated calcium channels, which triggers activation of Src family kinases. Src family kinases are required for phosphorylation of STAT3 at Tyr-705 and Ser-727. PTyr-705 is Janus kinase (JAK)-dependent, while PSer-727 is dependent on Akt, the Ser/Thr kinase. Both PTyr-705 and PSer-727 are necessary for nuclear translocation of STAT3 in these neurons. Chronic elevation of spontaneous activity by an A-type potassium blocker, 4-aminopyridine (4-AP), also induced the transient phosphorylation of STAT3, which after 4 h fell to basal levels despite the presence of 4-AP. These results suggest that phasic and chronic neuronal activation induce distinct molecular pathways, resulting in opposing regulation of STAT3 signal.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murase
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKay
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials; D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D026902:Potassium Channel Blockers; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D012694:Serine; D015761:4-Aminopyridine; D019061:src-Family Kinases
keywords: Akt; Erk1/2; JAK; STAT3; Src