IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+-channel and neurite elongation
Null mutations in the IL1-receptor accessory protein-like 1 gene (IL1RAPL1) are responsible for an inherited X-linked form of cognitive impairment (Carrie et al., Nat. Genet., 1999). The mouse homologue of IL1RAPL1 is expressed in neurons and glial cells of central nervous system. IL1RAPL1 belongs to a new class of the interleukin-1/toll receptor family. Bahi et al. (HMG, 2003) previously showed that IL1RAPL1 interacts by way of its 150-aa C-terminal domain with the neuronal calcium sensor-1 protein (NCS-1) and inhibits granules secretion, but the functional impact of the IL1RAPL1/NCS-1 interaction remains unknown. In collaboration with N. Vitale and B. Poulain's teams at INCI, Strasbourg, we recently demonstrate that IL1RAPL1 mediates through IL1RAPL1/NSC-1 interaction, a down-regulation of N-type voltage gated calcium channel (N-VGCC) activity that not only affect granule secretion but also has an impact on NGF-induced neurite outgrowth.
IL1RAPL1 mediates through IL1RAPL1/NSC-1 interaction a down-regulation (----|) of N-type voltage gated calcium channel (N-VGCC) activity that leads to inhibition of calcium-dependant exocytosis.
Most of physiological and biological properties of IL1RAPL1 protein remain largely unknown. Recent studies have demonstrated that IL1RAPL1 interacts with NCS-1, a neuronal calcium sensor widely expressed in neurons and the related chromaffin and PC12 cells. NCS-1 is implicated in the regulation of calcium-dependent exocytosis through its activation of PI4 kinase and PIP2 formation and we have previously demonstrate that expression of IL1RAPL1 in PC12 cells leads to a profound inhibition of ATP-induced growth hormone (GH) release. Moreover, NCS-1 modulates calcium channels trafficking and activity in various cellular models and has effects on synaptic transmission.
Here, we focus on IL1RAPL1 functions by studying the physiological impact of IL1RAPL1/NCS-1 interaction in PC12 cells, a well known model of both nerve growth factor (NGF)-induced neuronal differentiation and calcium-dependent exocytosis.
Electrophysiological studies of calcium currents in PC12 cells expressing IL1RAPL1 show that this protein inhibits N-VGCC activity. This phenotype is also founds when NSC-1 is overexpressed in PC12 cells. The data suggested that NCS-1 could mediate the negative regulation exerted by IL1RAPL1 on N-VGCC activity. In PC12 cells expressing IL1RAPL1, silencing of NCS-1 by siRNA leads to a total recovery of N-VGCC activity. IL1RAPL1 controls indirectly the functionality of N-VGCC by the way of NCS-1.
When treated with NGF, PC12 cells adopt neuron-like features displaying an increase in cell size, neurite elongation, and the insertion of Ca2+ channels, mainly of the N-type, in the plasma membrane. These effects have been shown to partially depend on NCS-1 activity. We therefore assessed a possible impact of IL1RAPL1/NCS-1 interaction on these NGF-induced effects. Expression of IL1RAPL1 in PC12 cells impairs NGF-induced differentiation. But the presence of IL1RAPL1 seems to lead to a deficit in neurite elongation rather than in neurite formation. This phenotype is rescued by NCS-1 down-regulation by siRNA in PC12 cells expressing IL1RAPL1.
The mechanisms underlying the negative regulatory action of IL1RAPL1/NCS-1 on calcium channels are yet unknown as those underlying the reduction of neurite elongation. Nevertheless, RT-PCR and immunocytochemistry experiments allow us to exclude any effect of IL1RAPL1 expression on either NCS-1 or N-VGCC main subunit expression and membrane localization of N-VGCC.
Ours data demonstrate the functional relevance of the interaction between IL1RAPL1 and NCS-1 in the regulation of N-VGCC activity and in neurite elongation. Because both IL1RAPL1 and NCS1 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.
Article
Gambino, F., Pavlowsky, A., Béglé, A., Dupont, J.L., Bahi, N., Courjaret, R., Gardette, R., Hadjkacem, H., Skala, H., Poulain, B., Chelly, J., Vitale, N., Humeau, Y. (2007) IL-receptor accessory protein-like 1 (ILRAPL), a protein involved in cognitive functions, regulates N-type Ca2+-channel and neurite elongation. Proc. Natl. Acad. Sci. USA, vol. 104, no. 21, 9063-9068
Contact
CHELLY JAMEL
PAVLOWSKY Alice
Institut Cochin
Département Génétique et développement
24, rue du Faubourg Saint-Jacques
75014 PARIS FRANCE
pavlowsky@cochin.inserm.fr