Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons.
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.
Díaz-Hernandez
Miguel
M
Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria, UCM, 28040-Madrid, Spain.
del Puerto
Ana
A
Díaz-Hernandez
Juan Ignacio
JI
Diez-Zaera
María
M
Lucas
José Javier
JJ
Garrido
Juan José
JJ
Miras-Portugal
María Teresa
MT
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D048708:Cell Growth Processes; D002460:Cell Line; D048429:Cell Size; D002478:Cells, Cultured; D015536:Down-Regulation; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D034622:RNA Interference; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction
C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D002118:Calcium