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. 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.
Gambino
Frédéric
F
Département Neurotransmission et Sécrétion Neuroendocrine, Institut des Neurosciences Cellulaires et Intégratives, Université Louis Pasteur, 5 Rue Blaise Pascal, 67084 Strasbourg, France.
Pavlowsky
Alice
A
Béglé
Aurélie
A
Dupont
Jean-Luc
JL
Bahi
Nadia
N
Courjaret
Raphael
R
Gardette
Robert
R
Hadjkacem
Hassen
H
Skala
Henriette
H
Poulain
Bernard
B
Chelly
Jamel
J
Vitale
Nicolas
N
Humeau
Yann
Y
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D004594:Electrophysiology; D005786:Gene Expression Regulation; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D051580:Neuronal Calcium-Sensor Proteins / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D051381:Rats
D020746:Calcium Channels, L-Type; C521481:IL1RAPL1 protein, rat; D053577:Interleukin-1 Receptor Accessory Protein; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C101464:frequenin calcium sensor proteins; D020932:Nerve Growth Factor