NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum

Curr Biol. 2016 Nov 21;26(22):2992-3003. doi: 10.1016/j.cub.2016.09.010. Epub 2016 Oct 20.


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.

Keywords: G proteins; GPCR signaling; addiction; neurofibromatosis; opioids; striatum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analgesics, Opioid / metabolism*
  • Animals
  • Female
  • Male
  • Mice
  • Neostriatum / metabolism
  • Neurofibromin 1 / genetics*
  • Neurofibromin 1 / metabolism
  • Neurons / metabolism
  • Protein Binding
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction*
  • ras Proteins / metabolism*


  • Analgesics, Opioid
  • Neurofibromin 1
  • Receptors, G-Protein-Coupled
  • ras Proteins