title: JNK3 couples the neuronal stress response to inhibition of secretory trafficking.
abstract: Secretory trafficking through the Golgi complex is critical for neuronal development, function, and stress response. Altered secretion is associated with the pathogenesis of various neurological diseases. We found that c-Jun amino-terminal kinase 3 (JNK3) inhibited secretory trafficking by promoting the depletion of phosphatidylinositol 4-phosphate (PI4P) in the Golgi complex of COS7 cells and primary rat neurons. Exposure of cultured primary rat neurons to excitotoxic concentrations of NMDA (N-methyl-d-aspartate), an agonist of a class of ionotropic glutamate receptors, or overexpression of zD17 (a palmitoyl transferase) resulted in JNK3 palmitoylation and association with the Golgi complex. Analysis of mutant constructs of JNK3 indicated that Golgi association was independent of its kinase activity but depended on its palmitoylation. The association of JNK3 with the Golgi in cultured neurons decreased the secretory trafficking of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 (glutamate receptor subunit 1), a component of ionotropic glutamate receptors found at glutamatergic synapses. Palmitoylated JNK3 bound to the phosphatase Sac1, increasing its abundance at the Golgi and thereby decreasing the abundance of PI4P, a lipid necessary for post-Golgi trafficking. Disrupting the JNK3-Sac1 interaction with two synthetic peptides prevented the loss of surface GluR1 and preserved synaptic integrity in cultured neurons exposed to NMDA. Together, our results suggest that JNK3 participates in an adaptive response to neuronal hyperexcitation by impeding secretory trafficking at the Golgi complex.
authors.affiliation: Brain Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada. photonyg@interchange.ubc.ca
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.forename: Jingyan
authors.initials: J
authors.lastname: Zhu
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.forename: Ainsley
authors.initials: A
authors.lastname: Coquinco
authors.forename: Yongting
authors.initials: Y
authors.lastname: Chen
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wen
authors.forename: Luba
authors.initials: L
authors.lastname: Kojic
authors.forename: William
authors.initials: W
authors.lastname: Jia
authors.forename: Max S
authors.initials: MS
authors.lastname: Cynader
mesh_terms: D000217:Acyltransferases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006056:Golgi Apparatus / Q000235:genetics; D000072181:Inositol Polyphosphate 5-Phosphatases; D054878:Lipoylation / Q000187:drug effects / Q000502:physiology; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: D000217:Acyltransferases; D018690:Excitatory Amino Acid Agonists; D000072181:Inositol Polyphosphate 5-Phosphatases; D048057:Mitogen-Activated Protein Kinase 10; D016202:N-Methylaspartate; D010455:Peptides; D010744:Phosphoric Monoester Hydrolases; D018091:Receptors, AMPA