Abstract | BACKGROUND: RESULTS: We recently discovered a new human alternatively spliced isoform of MOR (MOR1K) that is missing the N-terminal extracellular and first transmembrane domains, resulting in a 6TM GPCR variant. To characterize the pattern of cellular transduction pathways activated by this human MOR1K isoform, we conducted a series of pharmacological and molecular experiments. Results show that stimulation of MOR1K with morphine leads to excitatory cellular effects. In contrast to stimulation of MOR1, stimulation of MOR1K leads to increased Ca2+ levels as well as increased nitric oxide (NO) release. Immunoprecipitation experiments further reveal that unlike MOR1, which couples to the inhibitory Galphai/o complex, MOR1K couples to the stimulatory Galphas complex. CONCLUSION: The major MOR1 and the alternative MOR1K isoforms mediate opposite cellular effects in response to morphine, with MOR1K driving excitatory processes. These findings warrant further investigations that examine animal and human MORK1 expression and function following chronic exposure to opioids, which may identify MOR1K as a novel target for the development of new clinically effective classes of opioids that have high analgesic efficacy with diminished ability to produce tolerance, OIH, and other unwanted side-effects.
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Authors | Pavel Gris, Josee Gauthier, Philip Cheng, Dustin G Gibson, Denis Gris, Oskar Laur, John Pierson, Sean Wentworth, Andrea G Nackley, William Maixner, Luda Diatchenko |
Journal | Molecular pain
(Mol Pain)
Vol. 6
Pg. 33
(Jun 02 2010)
ISSN: 1744-8069 [Electronic] United States |
PMID | 20525224
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Analgesics, Opioid
- Protein Isoforms
- Receptors, Opioid, mu
- Nitric Oxide
- Morphine
- Cyclic AMP
- GTP-Binding Proteins
- Calcium
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Topics |
- Alternative Splicing
- Analgesics, Opioid
(metabolism, pharmacology)
- Animals
- COS Cells
- Calcium
(metabolism)
- Chlorocebus aethiops
- Cyclic AMP
(metabolism)
- GTP-Binding Proteins
(metabolism)
- Humans
- Morphine
(metabolism, pharmacology)
- Nitric Oxide
(metabolism)
- Protein Isoforms
(antagonists & inhibitors, genetics, metabolism)
- Receptors, Opioid, mu
(agonists, antagonists & inhibitors, genetics)
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