IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+-channel and neurite elongation

Frédéric Gambino, Alice Pavlowsky, Aurélie Béglé, Jean Luc Dupont, Nadia Bahi, Raphael Jean Courjaret, Robert Gardette, Hassen Hadjkacem, Henriette Skala, Bernard Poulain, Jamel Chelly, Nicolas Vitale, Yann Humeau

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Abstract

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.

Original languageEnglish
Pages (from-to)9063-9068
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number21
DOIs
Publication statusPublished - 22 May 2007
Externally publishedYes

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Keywords

  • Exocytosis
  • Neuronal calcium sensor-1
  • PC12 cells
  • X-linked mental retardation

ASJC Scopus subject areas

  • General

Cite this

Gambino, F., Pavlowsky, A., Béglé, A., Dupont, J. L., Bahi, N., Courjaret, R. J., Gardette, R., Hadjkacem, H., Skala, H., Poulain, B., Chelly, J., Vitale, N., & Humeau, Y. (2007). IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+-channel and neurite elongation. Proceedings of the National Academy of Sciences of the United States of America, 104(21), 9063-9068. https://doi.org/10.1073/pnas.0701133104