Gupta Swati, Bazargani Narges, Drew James, Howden Jack H, Modi Souvik, Al Awabdh Sana, Marie Hélène, Attwell David, Kittler Josef T
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT London, UK.
iScience. 2022 Mar 21;25(4):104127. doi: 10.1016/j.isci.2022.104127. eCollection 2022 Apr 15.
Astrocytic GLT-1 is the main glutamate transporter involved in glutamate buffering in the brain, pivotal for glutamate removal at excitatory synapses to terminate neurotransmission and for preventing excitotoxicity. We show here that the surface expression and function of GLT-1 can be rapidly modulated through the interaction of its N-terminus with the nonadrenergic imidazoline-1 receptor protein, Nischarin. The phox domain of Nischarin is critical for interaction and internalization of surface GLT-1. Using live super-resolution imaging, we found that glutamate accelerated Nischarin-GLT-1 internalization into endosomal structures. The surface GLT-1 level increased in Nischarin knockout astrocytes, and this correlated with a significant increase in transporter uptake current. In addition, Nischarin knockout in astrocytes is neuroprotective against glutamate excitotoxicity. These data provide new molecular insights into regulation of GLT-1 surface level and function and suggest new drug targets for the treatment of neurological disorders.
星形胶质细胞中的谷氨酸转运体-1（GLT-1）是大脑中参与谷氨酸缓冲的主要谷氨酸转运体，对于在兴奋性突触处清除谷氨酸以终止神经传递以及预防兴奋性毒性至关重要。我们在此表明，GLT-1的表面表达和功能可通过其N端与非肾上腺素能咪唑啉-1受体蛋白Nischarin的相互作用而迅速调节。Nischarin的phox结构域对于表面GLT-1的相互作用和内化至关重要。使用实时超分辨率成像，我们发现谷氨酸加速了Nischarin-GLT-1向内体结构的内化。在Nischarin基因敲除的星形胶质细胞中，表面GLT-1水平升高，这与转运体摄取电流的显著增加相关。此外，星形胶质细胞中的Nischarin基因敲除对谷氨酸兴奋性毒性具有神经保护作用。这些数据为GLT-1表面水平和功能的调节提供了新的分子见解，并为神经疾病的治疗提出了新的药物靶点。
