p38 MAPK and beta-arrestin 2 mediate functional interactions between endogenous micro-opioid and alpha2A-adrenergic receptors in neurons.
Formation of receptor complexes between micro-opioid and alpha2A-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 micro and alpha2A receptors in mouse dorsal root ganglion neurons. Acute application of the micro agonist [D-Ala2,N-MePhe4, Gly-ol5]enkephalin (DAMGO) or the alpha2 agonist clonidine inhibited voltage-gated Ca2+ currents in these neurons. Prolonged treatment with either DAMGO or clonidine induced a mutual cross-desensitization between micro and alpha2A receptor-mediated current inhibition. The cross-desensitization was closely associated with simultaneous internalization of micro and alpha2A receptors. Morphine, a mu agonist triggering little mu receptor endocytosis, induced neither cross-desensitization nor internalization of alpha2A receptors. Furthermore, inhibition of p38 MAPK prevented the cross-desensitization as well as cointernalization of micro and alpha2A receptors. Changes in receptor trafficking profiles suggested that p38 MAPK activity was required for initiating micro receptor internalization and maintaining possible micro-alpha2A association during their cointernalization. Finally, the micro-alpha2A cross-desensitization was absent in dorsal root ganglion neurons lacking beta-arrestin 2. These findings demonstrated p38 MAPK- and beta-arrestin 2-dependent cross-regulation between neuronal micro and alpha2A 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.
Tan
Miao
M
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.
Walwyn
Wendy M
WM
Evans
Christopher J
CJ
Xie
Cui-Wei
CW
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C547768:ADRA2A protein, human; C000605254:ARRB2 protein, human; C547769:Adra2a protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D018377:Neurotransmitter Agents; D018341:Receptors, Adrenergic, alpha-2; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D048051:p38 Mitogen-Activated Protein Kinases; D003000:Clonidine; D002118:Calcium