Prolonged stimulation of μ-opioid receptors produces β-arrestin-2-mediated heterologous desensitization of α(2)-adrenoceptor function in locus ceruleus neurons.
Prolonged agonist stimulation of the μ-opioid receptor (MOR) initiates receptor regulatory events that rapidly attenuate receptor-mediated signaling (homologous desensitization). Emerging evidence suggests that persistent MOR stimulation can also reduce responsiveness of effectors to other G-protein-coupled receptors, termed heterologous desensitization. However, the mechanisms by which heterologous desensitization is triggered by MOR stimulation are unclear. This study used whole-cell patch-clamp recordings of ligand activated G-protein-activated inwardly rectifying potassium channel currents in mouse brain slices containing locus ceruleus (LC) neurons to determine the effects of prolonged stimulation of MOR on α(2)-adrenoceptor (α(2)-AR) function. The results show distinct and sequential development of homologous and heterologous desensitization during persistent stimulation of MOR in LC neurons with Met(5)-enkephalin (ME). ME stimulation of MOR promoted rapid homologous desensitization that reached a steady state after 5 min and partially recovered over 30 min. Longer stimulation of MOR (10 min) induced heterologous desensitization of α(2)-AR function that exhibited slower recovery than homologous desensitization. Heterologous (but not homologous) desensitization required β-arrestin-2 (βarr-2) because it was nearly abolished in βarr-2-knockout (ko) mice. Heterologous (but not homologous) desensitization was also prevented by inhibition of ERK1/2 and c-Src signaling in wild-type (wt) mouse LC neurons. Heterologous desensitization may be physiologically relevant during exposure to high doses of opioids because α(2)-AR-mediated slow inhibitory postsynaptic currents were depressed in wt but not βarr-2 ko LC neurons after prolonged exposure to opioids. Together, these findings demonstrate a novel mechanism by which βarr-2 can regulate postsynaptic responsiveness to neurotransmitter release.
Discipline of Pharmacology and Brain and Mind Research Institute, University of Sydney, New South Wales, Australia.
Vu C
VC
Dang
Billy C
BC
Chieng
MacDonald J
MJ
Christie
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D004705:Endocytosis / Q000502:physiology; D004744:Enkephalin, Methionine / Q000378:metabolism; D008024:Ligands; D008125:Locus Coeruleus / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction; D055366:Synaptic Potentials / Q000502:physiology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
C000605258:Arrb2 protein, mouse; D019390:Arrestins; D008024:Ligands; D018377:Neurotransmitter Agents; D024661:Potassium Channels, Inwardly Rectifying; D018341:Receptors, Adrenergic, alpha-2; D043562:Receptors, G-Protein-Coupled; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D004744:Enkephalin, Methionine; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D009638:Norepinephrine