title: Arg kinase signaling in dendrite and synapse stabilization pathways: memory, cocaine sensitivity, and stress.
abstract: The Abl2/Arg nonreceptor tyrosine kinase is enriched in dendritic spines where it is essential for maintaining dendrite and synapse stability in the postnatal mouse brain. Arg is activated downstream of integrin α3β1 receptors and it regulates the neuronal actin cytoskeleton by directly binding F-actin and via phosphorylation of substrates including p190RhoGAP and cortactin. Neurons in mice lacking Arg or integrin α3β1 develop normally through postnatal day 21 (P21), however by P42 mice exhibit major reductions in dendrite arbor size and complexity, and lose dendritic spines and synapses. As a result, mice with loss of Arg and Arg-dependent signaling pathways have impairments in memory tasks, heightened sensitivity to cocaine, and vulnerability to corticosteroid-induced neuronal remodeling. Therefore, understanding the molecular mechanisms of Arg regulation may lead to therapeutic approaches to treat human psychiatric and neurodegenerative diseases in which neuronal structure is destabilized.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. Electronic address: meghan.kerrisk@yale.edu.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Kerrisk
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008568:Memory / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000201:enzymology* / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000201:enzymology*
chemical_list: C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D003042:Cocaine
keywords: Abl-related gene; Actin cytoskeleton; Arg; Ca(2+)-dependent phospholipid binding domain; CaLB; Cocaine; Corticosteroid; ECM; F-actin; Integrin α3β1; N-methyl-d-aspartate receptor; N-terminal acidic domain; NMDA; NTA; Neuronal stability; P21, P42; PH; SH2, SH3; Src homology domain 1,2; arg knockdown; argKD; extracellular matrix; filamentous actin; mEPSC; miniature evoked postsynaptic current; p120; p120RasGAP, 120kDa GTPase activating protein for Ras; p190; p190RhoGAP, 190kDa GTPase activating protein for Rho; pleckstrin homology domain; postnatal day 21, 42
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