title: Synaptic activity bidirectionally regulates a novel sequence-specific S-Q phosphoproteome in neurons.
abstract: Protein phosphorylation plays a critical role in neuronal transcription, translation, cell viability, and synaptic plasticity. In neurons, phospho-enzymes and specific substrates directly link glutamate release and post-synaptic depolarization to these cellular functions; however, many of these enzymes and their protein substrates remain uncharacterized or unidentified. In this article, we identify a novel, synaptically driven neuronal phosphoproteome characterized by a specific motif of serine/threonine-glutamine ([S/T]-Q, abbreviated as SQ). These SQ-containing substrates are predominantly localized to dendrites, synapses, the soma; and activation of this SQ phosphoproteome by bicuculline application is induced via calcium influx through L-type calcium channels. On the other hand, acute application of NMDA can inactivate this SQ phosphoproteome. We demonstrate that the SQ motif kinase Ataxia-telangiectasia mutated can also localize to dendrites and dendritic spines, in addition to other subcellular compartments, and is activated by bicuculline application. Pharmacology studies indicate that Ataxia-telangiectasia mutated and its sister kinase ataxia telangiectasia mutated and Rad3-related up-regulate these neuronal SQ substrates. Phosphoproteomics identified over 150 SQ-containing substrates whose phosphorylation is bidirectionally regulated by synaptic activity.
authors.affiliation: Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Siddoway
authors.forename: Hailong
authors.initials: H
authors.lastname: Hou
authors.forename: Hongtian
authors.initials: H
authors.lastname: Yang
authors.forename: Ronald
authors.initials: R
authors.lastname: Petralia
authors.forename: Houhui
authors.initials: H
authors.lastname: Xia
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011247:Pregnancy; D061251:Primary Cell Culture; D020543:Proteome / Q000502:physiology; D040901:Proteomics; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D020543:Proteome; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D002118:Calcium
keywords: L-type calcium channels; Phosphoproteomics; SQ motif; phosphorylation; synaptic activity