Article

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
ABSTRACT
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
receptors.

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Available from: Wendy Walwyn, Aug 04, 2014