Glycogen synthase kinase-3 beta (GSK-3 beta), a key enzyme involved in cellular apoptosis and in mood disorders, may constitute a molecular target of delta-opioid receptors. However, relatively little is known on how delta-opioid receptors affect the multiple signaling pathways regulating GSK-3 beta. In the present study, we show that activation of human delta-opioid receptors stably
expressed in Chinese hamster ovary (CHO) cells induced a rapid GSK-3 beta phosphorylation on Ser9 and a significant inhibition of the kinase activity. This effect was dependent on G proteins Gi/Go, unaffected by cell transfection with this website the G beta gamma scavenger transducin, required the Src non-receptor tyrosine kinase and the specific involvement of the alpha isoform of phosphatidylinositol 3-kinase. delta-Opioid agonists activated the protein kinase Akt in a Src-dependent manner and chemical inhibition of Akt or stable expression of a dominant negative
Akt1 mutant reduced the stimulation eFT-508 concentration of GSK-3 beta phosphorylation. Moreover, delta-opioid receptor regulation of Akt and GSK-3 beta was dependent on transphosphorylation and transactivation of platelet-derived growth factor and insulin-like growth factor-1 receptor tyrosine kinases. AMP-activated protein kinase (AMPK) activity was also required, as delta-opioid effects on Akt and GSK-3 beta were mimicked by the AMPK activator A-769662 and reduced by the AMPK inhibitor Compound C. Conversely, inhibition of protein kinase C isoforms, extracellular signal-regulated protein kinases 1/2 and mammalian target of rapamycin was without effect, although the latter two kinases were activated by delta-opioid agonists. The results identify Src-dependent transactivation of receptor tyrosine kinases as a key process in delta-opioid receptor inhibitory control of GSK-3
beta and reveal a novel delta-opioid regulatory mechanism mediated by AMPK.
This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’. (C) 2011 Elsevier Ltd. All rights reserved.”
“Objective: To report the results of aortic root reoperations after pulmonary autograft implantation.
Methods: Poziotinib mouse All consecutive patients in our prospective Ross research database were selected for analysis, and additional information for patients requiring reoperation was obtained from the hospital records.
Results: From 1988 to 2009, 155 pulmonary autograft operations were performed. During this period, 41 patients required reoperation for aortic root dilatation and/or autograft valve insufficiency, in 8 patients combined with pulmonary allograft dysfunction. The freedom from autograft reoperation rate was 86% (standard error, 3.3%) after 10 years and 52% (standard error, 6.6%) after 15 years. The median interval to reoperation was 15.3 years.