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The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 1995 Mar; Vol. 15 (3 Pt 2), pp. 2396-406. - Publication Year :
- 1995
-
Abstract
- Opioids are some of the most efficacious analgesics used in humans. Prolonged administration of opioids, however, often causes the development of drug tolerance, thus limiting their effectiveness. To explore the molecular basis of those mechanisms that may contribute to opioid tolerance, we have isolated a cDNA for the human mu opioid receptor, the target of such opioid narcotics as morphine, codeine, methadone, and fentanyl. The receptor encoded by this cDNA is 400 amino acids long with 94% sequence similarity to the rat mu opioid receptor. Transient expression of this cDNA in COS-7 cells produced high-affinity binding sites to mu-selective agonists and antagonists. This receptor displays functional coupling to a recently cloned G-protein-activated K+ channel. When both proteins were expressed in Xenopus oocytes, functional desensitization developed upon repeated stimulation of the mu opioid receptor, as observed by a reduction in K+ current induced by the second mu receptor activation relative to that induced by the first. The extent of desensitization was potentiated by both the multifunctional calcium/calmodulin-dependent protein kinase and protein kinase C. These results demonstrate that kinase modulation is a molecular mechanism by which the desensitization of mu receptor signaling may be regulated at the cellular level, suggesting that this cellular mechanism may contribute to opioid tolerance in humans.
- Subjects :
- Adolescent
Adult
Aged
Amino Acid Sequence
Animals
Binding, Competitive
Brain Chemistry
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Cell Line, Transformed
Chlorocebus aethiops
DNA, Complementary genetics
Drug Tolerance
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
Enkephalins metabolism
Female
GTP-Binding Proteins metabolism
Humans
Ion Channel Gating drug effects
Male
Middle Aged
Molecular Sequence Data
Oocytes
Phosphorylation
RNA, Messenger biosynthesis
Rats
Receptors, Opioid, mu genetics
Recombinant Fusion Proteins metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction drug effects
Xenopus laevis
Calcium-Calmodulin-Dependent Protein Kinases metabolism
Narcotics metabolism
Potassium Channels metabolism
Protein Kinase C metabolism
Protein Processing, Post-Translational drug effects
Receptors, Opioid, mu metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0270-6474
- Volume :
- 15
- Issue :
- 3 Pt 2
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 7891175