Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD, USA.
Eur J Neurosci. 2014 Feb;39(4):557-65. doi: 10.1111/ejn.12412. Epub 2013 Nov 6.
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.
信号转导子和转录激活子 3（STAT3）在出生后第一周内显著增加，并支持成熟海马神经元的存活。最近，我们报道了兴奋性的慢性升高导致 STAT3 信号的丧失，从而使神经元易受损伤。STAT3 信号的丧失是由于 Erk1/2 激活受损所致。虽然 overnight 活动升高会减弱 STAT3 信号，但短暂的低频刺激（诱导长时程抑制）已被证明可以激活 STAT3。在这里，我们研究了 STAT3 如何对成熟神经元的去极化做出反应。短暂的去极化会导致 STAT3 的瞬时激活：它通过 L 型电压门控钙通道诱导钙内流，从而触发 Src 家族激酶的激活。Src 家族激酶对于 STAT3 在 Tyr-705 和 Ser-727 位点的磷酸化是必需的。PTyr-705 依赖于 Janus 激酶（JAK），而 PSer-727 依赖于 Akt，即丝氨酸/苏氨酸激酶。PTyr-705 和 PSer-727 对于 STAT3 在这些神经元中的核转位都是必需的。通过 A 型钾通道阻断剂 4-氨基吡啶（4-AP）慢性升高自发性活动也会诱导 STAT3 的瞬时磷酸化，尽管存在 4-AP，但 4 小时后磷酸化水平降至基础水平。这些结果表明，阵发性和慢性神经元激活诱导不同的分子途径，从而导致 STAT3 信号的相反调节。
