Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine.
Chronic morphine causes the mu opioid receptor (MOR) to switch its coupling from Gi/o to Gs, resulting in excitatory signaling via both Galphas and its Gbetagamma dimer. Ultra-low-dose naloxone (NLX) prevents this switch and attenuates opioid tolerance and dependence. This protective effect is media...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19172190/?tool=EBI |
| _version_ | 1819025581348487168 |
|---|---|
| author | Hoau-Yan Wang Lindsay H Burns |
| author_facet | Hoau-Yan Wang Lindsay H Burns |
| author_sort | Hoau-Yan Wang |
| collection | DOAJ |
| description | Chronic morphine causes the mu opioid receptor (MOR) to switch its coupling from Gi/o to Gs, resulting in excitatory signaling via both Galphas and its Gbetagamma dimer. Ultra-low-dose naloxone (NLX) prevents this switch and attenuates opioid tolerance and dependence. This protective effect is mediated via a high-affinity interaction of NLX to a pentapeptide region in c-terminal filamin A (FLNA), a scaffolding protein interacting with MOR. In organotypic striatal slice cultures, we now show that acute morphine induces a dose-dependent Go-to-Gs coupling switch at 5 and 15 min that resolves by 1 hr. The acute Gs coupling induced by 100 microM morphine was completely prevented by co-treatment with 100 pM NLX, (+)NLX, or naltrexone (NTX), or their pentapeptide binding site (FLNA(2561-2565)), which we show can act as a decoy for MOR or bind to FLNA itself. All of these co-treatments presumably prevent the MOR-FLNA interaction. Since ultra-low-dose NTX also attenuates the addictive properties of opioids, we assessed striatal cAMP production and CREB phosphorylation at S(133). Correlating with the Gs coupling, acute morphine induced elevated cAMP levels and a several-fold increase in pS(133)CREB that were also completely blocked by NLX, NTX or the FLNA pentapeptide. We propose that acute, robust stimulation of MOR causes an interaction with FLNA that allows an initially transient MOR-Gs coupling, which recovers with receptor recycling but persists when MOR stimulation is repeated or prolonged. The complete prevention of this acute, morphine-induced MOR-Gs coupling by 100 pM NLX/NTX or 10 microM pentapeptide segment of FLNA further elucidates both MOR signaling and the mechanism of action of ultra-low-dose NLX or NTX in attenuating opioid tolerance, dependence and addictive potential. |
| first_indexed | 2024-12-21T05:12:57Z |
| format | Article |
| id | doaj.art-c1ca0630d8494c79a706a4a5ef23216a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T05:12:57Z |
| publishDate | 2009-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c1ca0630d8494c79a706a4a5ef23216a2022-12-21T19:15:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0141e428210.1371/journal.pone.0004282Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine.Hoau-Yan WangLindsay H BurnsChronic morphine causes the mu opioid receptor (MOR) to switch its coupling from Gi/o to Gs, resulting in excitatory signaling via both Galphas and its Gbetagamma dimer. Ultra-low-dose naloxone (NLX) prevents this switch and attenuates opioid tolerance and dependence. This protective effect is mediated via a high-affinity interaction of NLX to a pentapeptide region in c-terminal filamin A (FLNA), a scaffolding protein interacting with MOR. In organotypic striatal slice cultures, we now show that acute morphine induces a dose-dependent Go-to-Gs coupling switch at 5 and 15 min that resolves by 1 hr. The acute Gs coupling induced by 100 microM morphine was completely prevented by co-treatment with 100 pM NLX, (+)NLX, or naltrexone (NTX), or their pentapeptide binding site (FLNA(2561-2565)), which we show can act as a decoy for MOR or bind to FLNA itself. All of these co-treatments presumably prevent the MOR-FLNA interaction. Since ultra-low-dose NTX also attenuates the addictive properties of opioids, we assessed striatal cAMP production and CREB phosphorylation at S(133). Correlating with the Gs coupling, acute morphine induced elevated cAMP levels and a several-fold increase in pS(133)CREB that were also completely blocked by NLX, NTX or the FLNA pentapeptide. We propose that acute, robust stimulation of MOR causes an interaction with FLNA that allows an initially transient MOR-Gs coupling, which recovers with receptor recycling but persists when MOR stimulation is repeated or prolonged. The complete prevention of this acute, morphine-induced MOR-Gs coupling by 100 pM NLX/NTX or 10 microM pentapeptide segment of FLNA further elucidates both MOR signaling and the mechanism of action of ultra-low-dose NLX or NTX in attenuating opioid tolerance, dependence and addictive potential.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19172190/?tool=EBI |
| spellingShingle | Hoau-Yan Wang Lindsay H Burns Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine. PLoS ONE |
| title | Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine. |
| title_full | Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine. |
| title_fullStr | Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine. |
| title_full_unstemmed | Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine. |
| title_short | Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine. |
| title_sort | naloxone s pentapeptide binding site on filamin a blocks mu opioid receptor gs coupling and creb activation of acute morphine |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19172190/?tool=EBI |
| work_keys_str_mv | AT hoauyanwang naloxonespentapeptidebindingsiteonfilaminablocksmuopioidreceptorgscouplingandcrebactivationofacutemorphine AT lindsayhburns naloxonespentapeptidebindingsiteonfilaminablocksmuopioidreceptorgscouplingandcrebactivationofacutemorphine |