Document Detail


Phosphoinositide 3-kinase cascade facilitates mu-opioid desensitization in sensory neurons by altering G-protein-effector interactions.
MedLine Citation:
PMID:  14614088     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Signaling via G-protein-coupled receptors undergoes desensitization after prolonged agonist exposure. Here we investigated the role of phosphoinositide 3-kinase (PI3K) and its downstream pathways in desensitization of micro-opioid inhibition of neuronal Ca2+ channels. In cultured mouse dorsal root ganglion neurons, two mechanistically different forms of desensitization were observed after acute or chronic treatment with the micro agonist [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin (DAMGO). Chronic DAMGO desensitization was heterologous in nature and significantly attenuated by blocking the activity of PI3K or mitogen-activated protein kinase (MAPK). A combined application of PI3K and MAPK inhibitors showed no additive effect, suggesting that these two kinases act in a common pathway to facilitate chronic desensitization. Acute DAMGO desensitization, however, was not affected by the inhibitors. Furthermore, upregulation of the PI3K-Akt pathway in mutant mice lacking phosphatase and tensin homolog, a lipid phosphatase counteracting PI3K, selectively enhanced chronic desensitization in a PI3K- and MAPK-dependent manner. Using the prepulse facilitation (PPF) test, we further examined changes in the voltage-dependent component of DAMGO action that requires direct interactions between betagamma subunits of G-proteins and Ca2+ channels. DAMGO-induced PPF was diminished after chronic treatment, suggesting disruption of G-protein-channel interactions. Such disruption could occur at the postreceptor level, because chronic DAMGO also reduced GTPgammaS-induced PPF that was independent of receptor activation. Again, inhibition of PI3K or MAPK reduced desensitization of PPF. Our data suggest that the PI3Kcascade involving MAPK and Akt enhances micro-opioid desensitization via postreceptor modifications that interfere with G-protein-effector interactions.
Authors:
Miao Tan; Matthias Groszer; Aiko M Tan; Amy Pandya; Xin Liu; Cui-Wei Xie
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  23     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-11-17     Completed Date:  2003-12-08     Revised Date:  2012-06-04    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10292-301     Citation Subset:  IM    
Affiliation:
Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, Los Angeles, California 90024-1759, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism
Calcium Channels / drug effects,  metabolism
Cells, Cultured
Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
Enzyme Inhibitors / pharmacology
GTP-Binding Proteins / metabolism*
Ganglia, Spinal / cytology
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism
Neurons, Afferent / cytology,  drug effects,  metabolism*
PTEN Phosphohydrolase
Patch-Clamp Techniques
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism*
Phosphoric Monoester Hydrolases / deficiency,  genetics
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / antagonists & inhibitors,  metabolism
Proto-Oncogene Proteins c-akt
Receptors, Opioid, mu / agonists,  metabolism*
Signal Transduction / drug effects,  physiology
Tumor Suppressor Proteins / deficiency,  genetics
Grant Support
ID/Acronym/Agency:
NS38489/NS/NINDS NIH HHS; P50 DA005010/DA/NIDA NIH HHS; P50DA05010/DA/NIDA NIH HHS; R01AG17542/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Calcium Channels; 0/Enzyme Inhibitors; 0/Proto-Oncogene Proteins; 0/Receptors, Opioid, mu; 0/Tumor Suppressor Proteins; 100929-53-1/Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; 7440-70-2/Calcium; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.67/PTEN Phosphohydrolase; EC 3.6.1.-/GTP-Binding Proteins

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