KAN Research Institute, Kobe 650-0047, Japan.
Mol Cell Neurosci. 2013 Sep;56:234-43. doi: 10.1016/j.mcn.2013.06.003. Epub 2013 Jun 11.
The neuronal network is tightly regulated by a large variety of locally connected GABAergic neurons. Neuregulin1 (Nrg1) and its receptor ErbB4 are master regulators in the morphological and functional development of excitatory synapses in GABAergic neurons. We previously showed that the immunoglobulin-like cell adhesion molecule, nectin-like molecule-2 (Necl-2)/CADM1, interacts with the ErbB3 and ErbB4 receptors, and that the interaction of Necl-2 with ErbB3 inhibits the Nrg1-induced ErbB3/ErbB2 signaling in epithelial cells. Here, we examined the role of the interaction of Necl-2 with ErbB4 in GABAergic neurons. Necl-2 was co-expressed with ErbB4 in parvalbumin-positive GABAergic neurons in the mouse hippocampus and co-localized with ErbB4 at excitatory synapses. Necl-2 knockdown enhanced the Nrg1-induced phosphorylation of ErbB4. Moreover, overexpression of PTPN13, which is a tyrosine phosphatase bound to the cytoplasmic tail of Necl-2, suppressed the Nrg1-induced development of excitatory synapses in GABAergic neurons through the inhibition of ErbB4 activity. These results indicate that Necl-2 interacts with ErbB4 and regulates the development of excitatory synapses via the regulation of ErbB4 activity in GABAergic neurons.
神经元网络受到大量局部连接的 GABA 能神经元的严格调节。神经调节蛋白 1（Nrg1）及其受体 ErbB4 是 GABA 能神经元中兴奋性突触形态和功能发育的主要调节因子。我们之前曾表明，免疫球蛋白样细胞粘附分子 nectin-like molecule-2（Necl-2）/CADM1 与 ErbB3 和 ErbB4 受体相互作用，并且 Necl-2 与 ErbB3 的相互作用抑制了上皮细胞中 Nrg1 诱导的 ErbB3/ErbB2 信号传导。在这里，我们研究了 Necl-2 与 ErbB4 相互作用在 GABA 能神经元中的作用。Necl-2 在小鼠海马体的 parvalbumin 阳性 GABA 能神经元中与 ErbB4 共表达，并与兴奋性突触处的 ErbB4 共定位。Necl-2 的敲低增强了 Nrg1 诱导的 ErbB4 磷酸化。此外，过表达与 Necl-2 的细胞质尾巴结合的酪氨酸磷酸酶 PTPN13，通过抑制 ErbB4 活性，抑制了 Nrg1 诱导的 GABA 能神经元中兴奋性突触的发育。这些结果表明，Necl-2 与 ErbB4 相互作用，并通过调节 GABA 能神经元中 ErbB4 活性来调节兴奋性突触的发育。
