Gambino Frédéric, Pavlowsky Alice, Béglé Aurélie, Dupont Jean-Luc, Bahi Nadia, Courjaret Raphael, Gardette Robert, Hadjkacem Hassen, Skala Henriette, Poulain Bernard, Chelly Jamel, Vitale Nicolas, Humeau Yann
Département Neurotransmission et Sécrétion Neuroendocrine, Institut des Neurosciences Cellulaires et Intégratives, Université Louis Pasteur, 5 Rue Blaise Pascal, 67084 Strasbourg, France.
Proc Natl Acad Sci U S A. 2007 May 22;104(21):9063-8. doi: 10.1073/pnas.0701133104. Epub 2007 May 14.
Null mutations in the IL1-receptor accessory protein-like 1 gene (IL1RAPL1) are responsible for an inherited X-linked form of cognitive impairment. IL1RAPL1 protein physically interacts with neuronal calcium sensor-1 (NCS-1), but the functional impact of the IL1RAPL1/NCS-1 interaction remains unknown. Here, we demonstrate that stable expression of IL1RAPL1 in PC12 cells induces a specific silencing of N-type voltage-gated calcium channels (N-VGCC) activity that explains a secretion deficit observed in these IL1RAPL1 cells. Importantly, this modulation of VGCC activity is mediated by NCS-1. Indeed, a specific loss-of-function of N-VGCC was observed in PC12 cells overexpressing NCS-1, and a total recovery of N-VGCC activity was obtained by a down-regulation of NCS-1 in IL1RAPL1 cells. The functional relevance of the interaction between IL1RAPL1 and NCS-1 was also suggested by the reduction of neurite elongation observed in nerve growth factor (NGF)-treated IL1RAPL1 cells, a phenotype rescued by NCS-1 inactivation. Because both proteins are highly expressed in neurons, these results suggest that IL1RAPL1-related mental retardation could result from a disruption of N-VGCC and/or NCS-1-dependent synaptic and neuronal activities.
白细胞介素1受体辅助蛋白样1基因（IL1RAPL1）的无效突变导致一种遗传性X连锁认知障碍。IL1RAPL1蛋白与神经元钙传感器-1（NCS-1）发生物理相互作用，但IL1RAPL1/NCS-1相互作用的功能影响尚不清楚。在此，我们证明IL1RAPL1在PC12细胞中的稳定表达诱导N型电压门控钙通道（N-VGCC）活性特异性沉默，这解释了在这些IL1RAPL1细胞中观察到的分泌缺陷。重要的是，VGCC活性的这种调节由NCS-1介导。事实上，在过表达NCS-1的PC12细胞中观察到N-VGCC的特异性功能丧失，并且通过下调IL1RAPL1细胞中的NCS-1获得了N-VGCC活性的完全恢复。在神经生长因子（NGF）处理的IL1RAPL1细胞中观察到的神经突伸长减少也提示了IL1RAPL1与NCS-1之间相互作用的功能相关性，该表型通过NCS-1失活得以挽救。由于这两种蛋白在神经元中均高度表达，这些结果表明IL1RAPL1相关的智力迟钝可能是由N-VGCC和/或NCS-1依赖性突触及神经元活动的破坏所致。
