p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate

Coulson, E. J., May, L. M., Osborne, S. L., Reid, K., Underwood, C. K., Meunier, F. A., Bartlett, P. F. and Sah, P. (2008) p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate. Journal of Neuroscience, 28 1: 315-324. doi:10.1523/JNEUROSCI.2699-07.2008

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Author Coulson, E. J.
May, L. M.
Osborne, S. L.
Reid, K.
Underwood, C. K.
Meunier, F. A.
Bartlett, P. F.
Sah, P.
Title p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate
Formatted title
 p75 Neurotrophin Receptor Mediates Neuronal Cell Death by Activating GIRK Channels through Phosphatidylinositol 4,5-Bisphosphate
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
Publication date 2008-01-02
Year available 2008
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.2699-07.2008
Open Access Status File (Publisher version)
Volume 28
Issue 1
Start page 315
End page 324
Total pages 10
Editor John H. R. Maunsell
Place of publication United States
Publisher Neuroscience Society
Collection year 2009
Language eng
Subject C1
060103 Cell Development, Proliferation and Death
110902 Cellular Nervous System
730104 Nervous system and disorders
Abstract 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.
Keyword Animals
Animals, Newborn
Cell Death/physiology
Cells, Cultured
Cercopithecus Aethiops
Dose-response Relationship, Drug
Enzyme Inhibitors/pharmacology
G Protein-coupled Inwardly-rectifying Potassium Channels/ Physiology
Ganglia, Spinal/cytology
Green Fluorescent Proteins/metabolism
Membrane Potentials/drug Effects/physiology/radiation Effects
Mice, Inbred C57bl
Neurons/drug Effects/ Physiology
Patch-clamp Techniques/methods
Phosphatidylinositol 4,5-diphosphate/ Metabolism
Potassium Channel Blockers/pharmacology
Receptors, Nerve Growth Factor/ Physiology
Q-Index Code C1
Q-Index Status Confirmed Code

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Created: Wed, 19 Mar 2008, 09:44:12 EST