title: Palmitoylation of A-kinase anchoring protein 79/150 regulates dendritic endosomal targeting and synaptic plasticity mechanisms.
abstract: NMDA receptor-dependent long-term potentiation (LTP) and depression (LTD) are forms of synaptic plasticity underlying learning and memory that are expressed through increases and decreases, respectively, in dendritic spine size and AMPA receptor (AMPAR) phosphorylation and postsynaptic localization. The A-kinase anchoring protein 79/150 (AKAP79/150) signaling scaffold regulates AMPAR phosphorylation, channel activity, and endosomal trafficking associated with LTP and LTD. AKAP79/150 is targeted to dendritic spine plasma membranes by an N-terminal polybasic domain that binds phosphoinositide lipids, F-actin, and cadherin cell adhesion molecules. However, we do not understand how regulation of AKAP targeting controls AMPAR endosomal trafficking. Here, we report that palmitoylation of the AKAP N-terminal polybasic domain targets it to postsynaptic lipid rafts and dendritic recycling endosomes. AKAP palmitoylation was regulated by seizure activity in vivo and LTP/LTD plasticity-inducing stimuli in cultured rat hippocampal neurons. With chemical LTP induction, we observed AKAP79 dendritic spine recruitment that required palmityolation and Rab11-regulated endosome recycling coincident with spine enlargement and AMPAR surface delivery. Importantly, a palmitoylation-deficient AKAP79 mutant impaired regulation of spine size, endosome recycling, AMPAR trafficking, and synaptic potentiation. These findings emphasize the emerging importance of palmitoylation in controlling synaptic function and reveal novel roles for the AKAP79/150 signaling complex in dendritic endosomes.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Dove J
authors.initials: DJ
authors.lastname: Keith
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sanderson
authors.forename: Emily S
authors.initials: ES
authors.lastname: Gibson
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Woolfrey
authors.forename: Holly R
authors.initials: HR
authors.lastname: Robertson
authors.forename: Kyle
authors.initials: K
authors.lastname: Olszewski
authors.forename: Rujun
authors.initials: R
authors.lastname: Kang
authors.forename: Alaa
authors.initials: A
authors.lastname: El-Husseini
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'acqua
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D054878:Lipoylation / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology; D008297:Male; D009473:Neuronal Plasticity / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
chemical_list: D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; C415703:Akap5 protein, rat; D018091:Receptors, AMPA; D007608:Kainic Acid