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The Journal of Neuroscience, January 2, 2008, 28(1):315-324; doi:10.1523/JNEUROSCI.2699-07.2008

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Development/Plasticity/Repair
p75 Neurotrophin Receptor Mediates Neuronal Cell Death by Activating GIRK Channels through Phosphatidylinositol 4,5-Bisphosphate

Elizabeth J. Coulson,^1,2 Linda M. May,¹ Shona L. Osborne,² Kate Reid,¹ Clare K. Underwood,^1,2 Frederic A. Meunier,² Perry F. Bartlett,^1 * and Pankaj Sah^1,2 *

¹Queensland Brain Institute and ²School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia

Correspondence should be addressed to Elizabeth J. Coulson at the above address. Email: e.coulson{at}uq.edu.au

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.

Key words: nerve growth factor (NGF); regulated intramembrane proteolysis (RIP); apoptosis; Kir channel; neuronal death; phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂]; signal transduction

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Received June 14, 2007; revised Nov. 23, 2007; accepted Nov. 27, 2007.

Correspondence should be addressed to Elizabeth J. Coulson at the above address. Email: e.coulson{at}uq.edu.au

This article has been cited by other articles:

				A. Sotthibundhu, A. M. Sykes, B. Fox, C. K. Underwood, W. Thangnipon, and E. J. Coulson {beta}-Amyloid1-42 Induces Neuronal Death through the p75 Neurotrophin Receptor J. Neurosci., April 9, 2008; 28(15): 3941 - 3946. [Abstract] [Full Text] [PDF]

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