p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate.
The pan neurotrophin receptor p75(NTR) signals programmed cell death both during nervous system development and after neural trauma and disease in the adult. However, the molecular pathways by which death is mediated remain poorly understood. Here, we show that this cell death is initiated by activation of G-protein-coupled inwardly rectifying potassium (GIRK/Kir3) channels and a consequent potassium efflux. Death signals stimulated by neurotrophin-mediated cleavage of p75(NTR) activate GIRK channels through the generation and binding of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2/PIP2] to GIRK channels. Both GIRK channel activity and p75(NTR)-mediated neuronal death are inhibited by sequestration of PtdIns(4,5)P2 and application of GIRK channel inhibitors, whereas pertussis toxin treatment has no effect. Thus, p75(NTR) activates GIRK channels without the need for G(i/o)-proteins. Our results demonstrate a novel mode of activation of GIRK channels, representing an early step in the p75(NTR)-mediated cell death pathway and suggesting a function for these channels during nervous system development.
Coulson
Elizabeth J
EJ
Queensland Brain Institute and School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia. e.coulson@uq.edu.au
May
Linda M
LM
Osborne
Shona L
SL
Reid
Kate
K
Underwood
Clare K
CK
Meunier
Frederic A
FA
Bartlett
Perry F
PF
Sah
Pankaj
P
D000818:Animals; D000831:Animals, Newborn; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D014162:Transfection / Q000379:methods
D004791:Enzyme Inhibitors; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D026902:Potassium Channel Blockers; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D049452:Green Fluorescent Proteins; D020169:Caspases; D011188:Potassium