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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Cell Differentiation / drug effects
  • Electrophysiology
  • Gene Expression Regulation
  • Interleukin-1 Receptor Accessory Protein / genetics
  • Interleukin-1 Receptor Accessory Protein / metabolism*
  • Nerve Growth Factor / pharmacology
  • Neurites / drug effects
  • Neurites / metabolism*
  • Neuronal Calcium-Sensor Proteins / genetics
  • Neuronal Calcium-Sensor Proteins / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • PC12 Cells
  • Patch-Clamp Techniques
  • Rats


  • Calcium Channels, L-Type
  • IL1RAPL1 protein, rat
  • Interleukin-1 Receptor Accessory Protein
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • frequenin calcium sensor proteins
  • Nerve Growth Factor