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 Courjaret*,
- Robert Gardette§,
- Hassen Hadjkacem†,‡,
- Henriette Skala†,‡,
- Bernard Poulain*,
- Jamel Chelly†,‡,
- Nicolas Vitale*, and
- Yann Humeau*,¶
- *Département Neurotransmission et Sécrétion Neuroendocrine, Institut des Neurosciences Cellulaires et Intégratives, Unité Mixte de Recherche 7168/LC2, Centre National de la Recherche Scientifique and Université Louis Pasteur, 5 Rue Blaise Pascal, 67084 Strasbourg, France;
- †Institut Cochin, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, 75014 Paris, France;
- ‡Institut National de la Santé et de la Recherche Médicale, Unité 567, 75014 Paris, France; and
- §Institut National de la Santé et de la Recherche Médicale, Unité 549, IFR Broca Sainte Anne,2ter Rue d'Alesia, 75014 Paris, France
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Edited by Erwin Neher, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany, and approved April 9, 2007 (received for review February 7, 2007)
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.
Footnotes
- ¶To whom correspondence should be addressed. E-mail: humeau{at}neurochem.u-strasbg.fr
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Author contributions: F.G., J.C., N.V., and Y.H. designed research; F.G., A.P., A.B., J.-L.D., N.B., R.C., R.G., H.H., H.S., N.V., and Y.H. performed research; F.G., N.V., and Y.H. analyzed data; and B.P., J.C., N.V., and Y.H. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0701133104/DC1.
- Abbreviations:
- GH,
- growth hormone;
- HVA,
- high-voltage activated;
- IL1RAPL1,
- IL1-receptor accessory protein-like 1 gene;
- LVA,
- low-voltage activated;
- MR,
- mental retardation;
- NCS-1,
- neuronal calcium sensor-1;
- NGF,
- nerve growth factor;
- N-VGCC,
- N-type voltage-gated calcium channels;
- siRNA,
- small interfering RNA;
- YFP,
- yellow fluorescent protein.
- © 2007 by The National Academy of Sciences of the USA
