Activation of Pyk2 by CaM kinase II in cultured hypothalamic neurons and gonadotroph cells
Activation of Pyk2 by CaM kinase II in cultured hypothalamic neurons and gonadotroph cells
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DOI：
10.1002/jcp.27443
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发表时间：
2018-11
影响因子：
5.6
通讯作者：
Shiho Okitsu-Sakurayama;Sayomi Higa-Nakamine;Hidetsugu Torihara;H. Takahashi;S. Higashiyama;Hideyuki Yamamoto
中科院分区：
文献类型：
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作者：
Shiho Okitsu-Sakurayama;Sayomi Higa-Nakamine;Hidetsugu Torihara;H. Takahashi;S. Higashiyama;Hideyuki Yamamoto
促性腺激素释放激素（GnRH）由下丘脑GnRH神经元分泌，并刺激促性腺激素细胞和GnRH神经元中的GnRH受体。GnRH受体属于G蛋白偶联受体，刺激GnRH受体可激活细胞外信号调节蛋白激酶（ERK）。我们先前报道了Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaM kinase IIδ2）的δ2亚型参与培养的GnRH神经元（GT 1 -7细胞）中GnRH诱导的ERK激活。最近，我们发现GnRH处理GT 1 -7细胞激活富含脯氨酸的酪氨酸激酶2（Pyk 2），Pyk 2参与ERK激活。在目前的研究中，我们研究了CaM激酶IIδ2可能激活Pyk 2的可能性。敲低CaM激酶IIδ2和CaM激酶抑制剂KN 93可抑制GnRH诱导的Pyk 2活化。在培养的促性腺激素细胞（αT3 - 1细胞）的情况下，敲低CaM激酶II β 'e抑制GnRH诱导的Pyk 2激活。此外，我们的抑制剂研究表明Pyk 2和CaM激酶II参与了GnRH诱导的GT 1 -7细胞中proHB-EGF的脱落。这些结果表明，CaM激酶II通过Pyk 2激活和HB-EGF产生响应GnRH激活ERK通路。
Gonadotropin‐releasing hormone (GnRH) is secreted from hypothalamic GnRH neurons and stimulates a GnRH receptor in gonadotroph cells and GnRH neurons. The GnRH receptor belongs to the G‐protein‐coupled receptors, and stimulation of the GnRH receptor activates extracellular signal‐regulated protein kinase (ERK). We reported previously that the δ2 isoform of Ca2+/calmodulin‐dependent protein kinase II (CaM kinase IIδ2) was involved in GnRH‐induced ERK activation in cultured GnRH neurons (GT1–7 cells). Recently, we found that GnRH treatment of GT1–7 cells activated proline‐rich tyrosine kinase 2 (Pyk2), and Pyk2 was involved in ERK activation. In the current study, we examined the possibility that CaM kinase IIδ2 might activate Pyk2. Knockdown of CaM kinase IIδ2 and KN93, an inhibitor of CaM kinases, inhibited the GnRH‐induced activation of Pyk2. In the case of cultured gonadotroph cells (αT3‐1 cells), knockdown of CaM kinase IIβ’e inhibited GnRH‐induced Pyk2 activation. In addition, our inhibitor studies indicated that Pyk2 and CaM kinase II were involved in the GnRH‐induced shedding of proHB‐EGF in GT1–7 cells. These results suggested that CaM kinase II activated the ERK pathway through Pyk2 activation and HB‐EGF production in response to GnRH.