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Title: | Calcium/calmodulin-dependent protein kinase II supports morphine antinociceptive tolerance by phosphorylation of glycosylated phosducin-like protein |
Authors: | Sánchez-Blázquez, Pilar ![]() ![]() ![]() |
Issue Date: | 2008 |
Publisher: | Pergamon Press |
Citation: | Neuropharmacology 54: 319- 330 (2008) |
Abstract: | The long isoform of the phosducin-like protein (PhLPl) is widely expressed in the brain and it is thought to influence G-protein signalling by regulating the activity of Gβγ dimers. We show that in the mature nervous system, PhLPl exists as both a 38 kDa non-glycosylated isoform and as glycosylated isoforms of about 45, 100 and 150 kDa. Additionally, neural PhLPl is subject to serine phosphorylation, which augments upon the activation of Mu-opioid receptors (MORs), as does its association with Gβγ subunits and 14-3-3 proteins. While the intracerebroventricular (icv) administration of morphine to mice rapidly reduced the association of MORs with G proteins, it increased the serine phosphorylation of these receptors. Moreover, activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) accumulated in the MOR environment and phosphorylated PhLPl was seen to co-precipitate with these opioid receptors. Opioid-induced phosphorylation of PhLPl was impaired by inhibiting the activity of CaMKII and, in these circumstances, the association of PhLPl with Gβγ dimers and 14-3-3 proteins was diminished. Furthermore, these events were coupled with the recovery of G protein regulation by the MORs, while there was a decrease in serine phosphorylation of these receptors and morphine antinociceptive tolerance diminished. It seems that CaMKII phosphorylation of PhLPl stabilizes the PhLPl·Gβγ complex by promoting its binding to 14-3-3 proteins. When this complex fails to bind to 14-3-3 proteins, the association of PhLPl with Gβγ is probably disrupted by GαGDP subunits and the MORs recover control on G proteins. © 2007 Elsevier Ltd. All rights reserved. |
URI: | http://hdl.handle.net/10261/63344 |
DOI: | 10.1016/j.neuropharm.2007.10.002 |
Identifiers: | doi: 10.1016/j.neuropharm.2007.10.002 issn: 0028-3908 |
Appears in Collections: | (IC) Artículos |
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