TY - JOUR T1 - Prolonged Stimulation of μ-opioid Receptors Produces β-arrestin-2 Mediated Heterologous Desensitization of α<sub>2</sub>-adrenoceptor Function in Locus Coeruleus Neurons JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.079350 SP - mol.112.079350 AU - Vu C Dang AU - Billy C Chieng AU - Macdonald J Christie Y1 - 2012/01/01 UR - http://molpharm.aspetjournals.org/content/early/2012/06/11/mol.112.079350.abstract N2 - 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 (GPCRs), 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 GIRK currents in mouse brain slices containing LC neurons to determine the effects of prolonged stimulation of MOR on α2-adrenoceptor (α2-AR) function. The results show distinct and sequential development of homologous and heterologous desensitization during persistent stimulation of MOR in LC neurons with Met5-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 α2-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 (k.o.) mice. Heterologous (but not homologous) desensitization was also prevented by inhibition of ERK1/2 and c-Src signaling in wild-type (w.t.) mouse LC neurons. Heterologous desensitization may be physiologically relevant during exposure to high doses of opioids because α2-AR mediated slow inhibitory post-synaptic currents were depressed in w.t. but not βarr-2 k.o. LC neurons after prolonged exposure to opioids. Together, these findings demonstrate a novel mechanism by which βarr-2 can regulate post-synaptic responsiveness to neurotransmitter release. ER -