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

Abstract

SUMMARY It is well recognized that, 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 identified a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gβγ subunits in the striatum. We found that binding of Gβγ to NF1 inhibited its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevented the opioid receptor induced activation of Ras and eliminated 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.

Anti-Inflammatory Effects of Huangqin Decoction on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice Through Regulation of the Gut Microbiota and Suppression of the Ras-PI3K-Akt-HIF-1α and NF-κB Pathways

“…Activation of the TLR4 receptor results in activation of Ras, which signals through PI3K and Akt (Yoo et al, 2017). GPCR are activated by short-chain fatty acids (SCFA), which are metabolic products of bacteria (Sun et al, 2017), resulting in activation of Ras and PLC (Xie et al, 2016). Phospholipase C regulates activation of class I PI3K (Sabine et al, 2012).…”

Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila

“…These disorders emerge early in development and may involve both dysregulations of developmental processes and alterations in acute signaling/neuronal function in the developed nervous system. Nf1 has been observed to have important functions in adult mice and flies [14,19,27,28], and some phenotypes can be rescued by acute pharmacological treatment in adult animals [65]. Nonetheless, our data suggest that Nf1 loss disrupts a distributed set of microcircuits during a critical developmental window.…”

“…Neurofibromin acts as a GTPase-activating protein (GAP) for Ras, thus reducing active Ras signaling [12][13][14]. In addition to this major role in Ras signaling, neurofibromin has also been implicated in G protein-coupled receptor signal transduction, modulation of cAMP levels, and dopaminergic circuit function [15][16][17][18][19][20][21]. These pathways modulate both developmental processes, such as cell proliferation, migration, fate specification, apoptosis, and morphology, as well as cellular physiology and plasticity in adults [22,23].…”

Neurofibromin Structure, Functions and Regulation

“…Deletion of neurofibromin resulted in an increase in Ras baseline activity but abolished the opioid receptor-induced activation of Ras. This mechanism suggests a role for neurofibromin in drug addiction [132].…”

“…Xie et al (2016) [132] described a signaling mechanism in which GPCRs (opioid receptors) activate Ras-AKT-mTOR signaling in the striatum and showed that neurofibromin is required for the cross talk between GPCRs (opioid receptors) and Ras activation. Indeed, upon activation of opioid receptors by morphine, the released Gβγ subunits interact with the SecPH domain of neurofibromin and inhibit its Ras-GAP activity.…”