PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes

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 a (PI4KII alpha) 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 PI4KII alpha (Ser(5) and Ser(47)), 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 PI4KII alpha and its cargo proteins for redistribution throughout the cell. Importantly, a reduction in PI4KII alpha expression or phosphorylation increases alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression at the surface of hippocampal neurons. These studies implicate signalling between GSK3 and PI4KII alpha as a novel regulator of vesicular trafficking and neurotransmission in the brain.