title: NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum.
abstract: It is well recognized that G-protein-coupled receptors (GPCRs) can activate Ras-regulated kinase pathways to produce lasting changes in neuronal function. Mechanisms by which GPCRs transduce these signals and their relevance to brain disorders are not well understood. Here, we identify a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gβγ subunits in the striatum. We find that binding of Gβγ to NF1 inhibits its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevents the opioid-receptor-induced activation of Ras and eliminates its coupling to Akt-mTOR-signaling pathway. By acting in the striatal medium spiny neurons of the direct pathway, NF1 regulates opioid-induced changes in Ras activity, thereby sensitizing mice to psychomotor and rewarding effects of morphine. These results delineate a novel mechanism of GPCR signaling to Ras pathways and establish a critical role of NF1 in opioid addiction.
authors: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors: Keqiang
authors: K
authors: Xie
authors: Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Jupiter, FL 33458, USA.
authors: Lesley A
authors: LA
authors: Colgan
authors: Department of Metabolism and Aging, The Scripps Research Institute, 120 Scripps Way, Jupiter, FL 33458, USA.
authors: Maria T
authors: MT
authors: Dao
authors: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors: Brian S
authors: BS
authors: Muntean
authors: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors: Laurie P
authors: LP
authors: Sutton
authors: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors: Cesare
authors: C
authors: Orlandi
authors: Department of Ophthalmology, University of Florida, 1395 Center Drive, Gainesville, FL 32610, USA.
authors: Sanford L
authors: SL
authors: Boye
authors: Department of Ophthalmology, University of Florida, 1395 Center Drive, Gainesville, FL 32610, USA.
authors: Shannon E
authors: SE
authors: Boye
authors: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors: Chien-Cheng
authors: CC
authors: Shih
authors: Department of Neurology, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
authors: Yuqing
authors: Y
authors: Li
authors: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors: Baoji
authors: B
authors: Xu
authors: Department of Metabolism and Aging, The Scripps Research Institute, 120 Scripps Way, Jupiter, FL 33458, USA.
authors: Roy G
authors: RG
authors: Smith
authors: Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Jupiter, FL 33458, USA.
authors: Ryohei
authors: R
authors: Yasuda
authors: Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address: kirill@scripps.edu.
authors: Kirill A
authors: KA
authors: Martemyanov
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D025542:Neurofibromin 1; D043562:Receptors, G-Protein-Coupled; D018631:ras Proteins
keywords: G proteins; GPCR signaling; addiction; neurofibromatosis; opioids; striatum