title: A prolyl-isomerase mediates dopamine-dependent plasticity and cocaine motor sensitization.
abstract: Synaptic plasticity induced by cocaine and other drugs underlies addiction. Here we elucidate molecular events at synapses that cause this plasticity and the resulting behavioral response to cocaine in mice. In response to D1-dopamine-receptor signaling that is induced by drug administration, the glutamate-receptor protein metabotropic glutamate receptor 5 (mGluR5) is phosphorylated by microtubule-associated protein kinase (MAPK), which we show potentiates Pin1-mediated prolyl-isomerization of mGluR5 in instances where the product of an activity-dependent gene, Homer1a, is present to enable Pin1-mGluR5 interaction. These biochemical events potentiate N-methyl-D-aspartate receptor (NMDAR)-mediated currents that underlie synaptic plasticity and cocaine-evoked motor sensitization as tested in mice with relevant mutations. The findings elucidate how a coincidence of signals from the nucleus and the synapse can render mGluR5 accessible to activation with consequences for drug-induced dopamine responses and point to depotentiation at corticostriatal synapses as a possible therapeutic target for treating addiction.
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Joo Min
authors.initials: JM
authors.lastname: Park
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Hu
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Milshteyn
authors.forename: Ping-Wu
authors.initials: PW
authors.lastname: Zhang
authors.forename: Chester G
authors.initials: CG
authors.lastname: Moore
authors.forename: Sungjin
authors.initials: S
authors.lastname: Park
authors.forename: Michael C
authors.initials: MC
authors.lastname: Datko
authors.forename: Racquel D
authors.initials: RD
authors.lastname: Domingo
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Reyes
authors.forename: Xiaodong J
authors.initials: XJ
authors.lastname: Wang
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Etzkorn
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kern
authors.forename: David J
authors.initials: DJ
authors.lastname: Linden
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D017774:Long-Term Potentiation; D051379:Mice; D008969:Molecular Sequence Data; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003042:Cocaine; D004298:Dopamine; D000072233:Homer Scaffolding Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C000606850:Pin1 protein, mouse
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