The Neuroscience Institute of Montpellier, INM, INSERM UMR1051, University of Montpellier, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France.
The Neuroscience Institute of Montpellier, INM, INSERM UMR1051, University of Montpellier, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France; Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes, University of Montpellier, 4 Rue du Professeur Robert Debré, 30029 Nîmes, France.
Cell Rep. 2020 Feb 25;30(8):2581-2593.e7. doi: 10.1016/j.celrep.2020.02.001.
Neuronal Ca entry elicited by electrical activity contributes to information coding via activation of K and Cl channels. While Ca-dependent K channels have been extensively studied, the molecular identity and role of Ca-activated Cl channels (CaCCs) remain unclear. Here, we demonstrate that TMEM16F governs a Ca-activated Cl conductance in spinal motoneurons. We show that TMEM16F is expressed in synaptic clusters facing pre-synaptic cholinergic C-boutons in α-motoneurons of the spinal cord. Mice with targeted exon deletion in Tmem16f display decreased motor performance under high-demanding tasks attributable to an increase in the recruitment threshold of fast α-motoneurons. Remarkably, loss of TMEM16F function in a mouse model of amyotrophic lateral sclerosis (ALS) significantly reduces expression of an activity-dependent early stress marker and muscle denervation, delays disease onset, and preserves muscular strength only in male ALS mice. Thus, TMEM16F controls motoneuron excitability and impacts motor resistance as well as motor deterioration in ALS.
神经元电活动引起的钙离子内流通过激活钾和氯离子通道有助于信息编码。虽然钙依赖性钾通道已得到广泛研究，但钙激活氯离子通道（CaCCs）的分子身份和作用仍不清楚。在这里，我们证明 TMEM16F 控制脊髓运动神经元中的钙激活氯离子电导。我们表明，TMEM16F 在脊髓 α-运动神经元中面对前突触胆碱能 C-末梢的突触簇中表达。在 Tmem16f 中靶向外显子缺失的小鼠在高要求任务下的运动表现下降，这归因于快速 α-运动神经元募集阈值的增加。值得注意的是，在肌萎缩侧索硬化症 (ALS) 的小鼠模型中丧失 TMEM16F 功能显著降低了活性依赖性早期应激标志物的表达和肌肉去神经支配，延迟了疾病发作，并仅在雄性 ALS 小鼠中保留了肌肉力量。因此，TMEM16F 控制运动神经元兴奋性，并影响 ALS 中的运动抵抗和运动恶化。
