p38 MAPK and -Arrestin 2 Mediate Functional Interactions between Endogenous -Opioid and 2A-Adrenergic Receptors in Neurons

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90024-1759, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2009; 284(10):6270-81. DOI: 10.1074/jbc.M806742200
Source: PubMed


Formation of receptor complexes between μ-opioid and α2A-adrenergic receptors has been demonstrated in transfected cells. The functional significance and underlying mechanisms of
such receptor interactions remain to be determined in neuronal systems. We examined functional interactions between endogenous
μ and α2A receptors in mouse dorsal root ganglion neurons. Acute application of the μ agonist [d-Ala2,N-MePhe4, Gly-ol5]enkephalin (DAMGO) or the α2 agonist clonidine inhibited voltage-gated Ca2+ currents in these neurons. Prolonged treatment with either DAMGO or clonidine induced a mutual cross-desensitization between
μ and α2A receptor-mediated current inhibition. The cross-desensitization was closely associated with simultaneous internalization
of μ and α2A receptors. Morphine, a μ agonist triggering little μ receptor endocytosis, induced neither cross-desensitization nor internalization
of α2A receptors. Furthermore, inhibition of p38 MAPK prevented the cross-desensitization as well as cointernalization of μ and
α2A receptors. Changes in receptor trafficking profiles suggested that p38 MAPK activity was required for initiating μ receptor
internalization and maintaining possible μ-α2A association during their cointernalization. Finally, the μ-α2A cross-desensitization was absent in dorsal root ganglion neurons lacking β-arrestin 2. These findings demonstrated p38 MAPK-
and β-arrestin 2-dependent cross-regulation between neuronal μ and α2A receptors. By promoting receptor cross-desensitization and cointernalization, such functional interactions may serve as negative
feedback mechanisms triggered by prolonged agonist exposure to modulate the signaling of functionally related G protein-coupled

Download full-text


Available from: Wendy Walwyn, Aug 04, 2014
  • Source
    • "In addition to a number of G i/o -coupled GPCRs, these neurons also express the nonvisual arrestins (Komori et al., 1999). Of the two isoforms , b-arrestin 2 is known to regulate the function of some G i/o -coupled GPCRs in DRG neurons (Tan et al., 2009; Walwyn et al., 2007). However, whether b-arr1 regulates the function of these GPCRs has not been established. "
    [Show abstract] [Hide abstract]
    ABSTRACT: G-protein-coupled receptors (GPCRs) are typically present in a basal, inactive state but, when bound to an agonist, activate downstream signaling cascades. In studying arrestin regulation of opioid receptors in dorsal root ganglia (DRG) neurons, we find that agonists of delta opioid receptors (δORs) activate cofilin through Rho-associated coiled-coil-containing protein kinase (ROCK), LIM domain kinase (LIMK), and β-arrestin 1 (β-arr1) to regulate actin polymerization. This controls receptor function, as assessed by agonist-induced inhibition of voltage-dependent Ca(2+) channels in DRGs. Agonists of opioid-receptor-like receptors (ORL1) similarly influence the function of this receptor through ROCK, LIMK, and β-arr1. Functional evidence of this cascade was demonstrated in vivo, where the behavioral effects of δOR or ORL1 agonists were enhanced in the absence of β-arr1 or prevented by inhibiting ROCK. This pathway allows δOR and ORL1 agonists to rapidly regulate receptor function.
    Full-text · Article · Nov 2013 · Cell Reports
  • Source
    • "Following a single, 20 min session of SDS, mice showed an increase in phospho-p38 immunoreactivity (pp38-ir) in the DRN (Figures 1A and 1A 1 ). G protein coupled receptor activation can lead to p38 MAPK phosphorylation via recruitment of arrestin-dependent pathways (Tan et al., 2009; Gong et al., 2008), and activation of the dynorphin/kappa opioid receptor (KOR) system was shown to increase pp38-ir by this mechanism (Bruchas et al., 2006, 2007). Consistent with this concept, the increase in pp38-ir caused by SDS was prevented by blocking endogenous dynorphin activation of KOR with the selective antagonist norbinaltorphimine (norBNI) (Figures 1A and 1A 1 ). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Maladaptive responses to stress adversely affect human behavior, yet the signaling mechanisms underlying stress-responsive behaviors remain poorly understood. Using a conditional gene knockout approach, the α isoform of p38 mitogen-activated protein kinase (MAPK) was selectively inactivated by AAV1-Cre-recombinase infection in specific brain regions or by promoter-driven excision of p38α MAPK in serotonergic neurons (by Slc6a4-Cre or ePet1-Cre) or astrocytes (by Gfap-CreERT2). Social defeat stress produced social avoidance (a model of depression-like behaviors) and reinstatement of cocaine preference (a measure of addiction risk) in wild-type mice, but not in mice having p38α MAPK selectively deleted in serotonin-producing neurons of the dorsal raphe nucleus. Stress-induced activation of p38α MAPK translocated the serotonin transporter to the plasma membrane and increased the rate of transmitter uptake at serotonergic nerve terminals. These findings suggest that stress initiates a cascade of molecular and cellular events in which p38α MAPK induces a hyposerotonergic state underlying depression-like and drug-seeking behaviors.
    Full-text · Article · Aug 2011 · Neuron
  • Source
    • "An interesting difference between the morphine vs DAMGO-activated mu opioid receptors is a ligand-dependent interaction with the α 2A adrenergic receptor. Our data suggest that in DRG neurons this ligand-dependent receptorreceptor interaction is p38, β-arrestin 2 and possibly internalization-dependent. DAMGO, an internalizing mu receptor agonist, results in both internalization and desensitization of the α 2A receptor whereas morphine, a non-internalizing mu receptor agonist, neither internalizes nor desensitizes the α 2A receptor (Tan et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies.
    Full-text · Article · Feb 2010 · Drug and alcohol dependence
Show more