Glycogen synthase kinase 3 (GSK3) is essential for normal development and function of the central nervous system. It is especially important for regulating neurotransmission, although the downstream substrates mediating this function are not yet clear. In the present paper, we report the lipid kinase phosphatidylinositol 4-kinase II α (PI4KIIα) is a novel substrate of GSK3 that regulates trafficking and cell-surface expression of neurotransmitter receptors in neurons. GSK3 phosphorylates two distinct sites in the N-terminus of PI4KIIα (Ser5 and Ser47), promoting binding to the adaptor protein 3 (AP-3) complex for trafficking to the lysosome to be degraded. Blocking phosphorylation reduces trafficking to the lysosome, stabilizing PI4KIIα and its cargo proteins for redistribution throughout the cell. Importantly, a reduction in PI4KIIα expression or phosphorylation increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression at the surface of hippocampal neurons. These studies implicate signalling between GSK3 and PI4KIIα as a novel regulator of vesicular trafficking and neurotransmission in the brain.
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November 2014
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Research Article|
October 23 2014
PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes
James W. Robinson;
James W. Robinson
*Neurosignalling and Mood Disorders Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
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Iryna Leshchyns’ka;
Iryna Leshchyns’ka
†School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
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Hovik Farghaian;
Hovik Farghaian
*Neurosignalling and Mood Disorders Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
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William E. Hughes;
William E. Hughes
‡Diabetes and Obesity Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
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Vladimir Sytnyk;
Vladimir Sytnyk
†School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
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Graham G. Neely;
Graham G. Neely
1
§Functional Genomics Research Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
1Correspondence may be addressed to either of these authors (email g.neely@garvan.org.au or a.cole@garvan.org.au).
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Adam R. Cole
Adam R. Cole
1
*Neurosignalling and Mood Disorders Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
1Correspondence may be addressed to either of these authors (email g.neely@garvan.org.au or a.cole@garvan.org.au).
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Biochem J (2014) 464 (1): 145–156.
Article history
Received:
April 15 2014
Revision Received:
July 17 2014
Accepted:
August 01 2014
Accepted Manuscript online:
August 01 2014
Citation
James W. Robinson, Iryna Leshchyns’ka, Hovik Farghaian, William E. Hughes, Vladimir Sytnyk, Graham G. Neely, Adam R. Cole; PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes. Biochem J 15 November 2014; 464 (1): 145–156. doi: https://doi.org/10.1042/BJ20140497
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