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First published online November 5, 2008
doi: 10.1242/10.1242/jcs.034082

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Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons

Miguel Díaz-Hernandez^1,2,*, Ana del Puerto^3,4,*, Juan Ignacio Díaz-Hernandez^1,*, María Diez-Zaera¹, José Javier Lucas^2,4, Juan José Garrido^2,3,4, and María Teresa Miras-Portugal^1,

¹ Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria, UCM, 28040-Madrid, Spain
² CIBERNED, Centro Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Spain
³ Departamento de Neurobiología Celular Molecular y del Desarrollo, Instituto Cajal, CSIC, 28002-Madrid, Spain
⁴ Centro de Biología Molecular `Severo Ochoa', CSIC-UAM, Nicolás Cabrera, 1, 28049-Madrid, Spain

Author for correspondence (e-mail: jjgarrido{at}cbm.uam.es)

Author for correspondence (e-mail: mtmiras{at}vet.ucm.es)

Accepted 12 August 2008

During the establishment of neural circuits, the axons of neurons grow towards their target regions in response to both positive and negative stimuli. Because recent reports show that Ca²⁺ transients in growth cones negatively regulate axonal growth, we studied how ionotropic ATP receptors (P2X) might participate in this process. Our results show that exposing cultured hippocampal neurons to ATP induces Ca²⁺ transients in the distal domain of the axon and the concomitant inhibition of axonal growth. This effect is mediated by the P2X7 receptor, which is present in the growth cone of the axon. Pharmacological inhibition of P2X7 or its silencing by shRNA interference induces longer and more-branched axons, coupled with morphological changes to the growth cone. Our data suggest that these morphological changes are induced by a signalling cascade in which CaMKII and FAK activity activates PI3-kinase and modifies the activity of its downstream targets. Thus, in the absence or inactivation of P2X7 receptor, axons grow more rapidly and form more branches in cultured hippocampal neurons, indicative that ATP exerts a negative influence on axonal growth. These data suggest that P2X7 antagonists have therapeutic potential to promote axonal regeneration.

Key words: P2X7, Brilliant Blue G, Axonal growth, Axonal branching, CaMKII, FAK, GSK3

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