10098843

pubmed:Citation

4

To develop a malleable system to model the well-described, physiological interactions between Gq/11 - coupled receptor and Gi/o-coupled receptor signaling, we coexpressed the endothelin A receptor, the mu-opioid receptor, and the G protein-coupled inwardly rectifying potassium channel (Kir 3) heteromultimers in Xenopus laevis oocytes. Activation of the Gi/o-coupled mu-opioid receptor strongly increased Kir 3 channel current, whereas activation of the Gq/11-coupled endothelin A receptor inhibited the Kir 3 response evoked by mu-opioid receptor activation. The magnitude of the inhibition of Kir 3 was channel subtype specific; heteromultimers composed of Kir 3.1 and Kir 3.2 or Kir 3.1 and Kir 3.4 were significantly more sensitive to the effects of endothelin-1 than heteromultimers composed of Kir 3.1 and Kir 3.5. The difference in sensitivity of the heteromultimers suggests that the endothelin-induced inhibition of the opioid- activated current was caused by an effect at the channel rather than at the opioid receptor. The endothelin-1-mediated inhibition was mimicked by arachidonic acid and blocked by the phospholipase A2 inhibitor arachidonoyl trifluoromethyl ketone. Consistent with a possible phospholipase A2-mediated mechanism, the endothelin-1 effect was blocked by calcium chelation with BAPTA-AM and was not affected by kinase inhibition by either staurosporine or genistein. The data suggest the hypothesis that Gq/11-coupled receptor activation may interfere with Gi/o-coupled receptor signaling by the activation of phospholipase A2 and subsequent inhibition of effector function by a direct effect of an eicosanoid on the channel.

eng

IM

MEDLINE

0022-3042

Print

NLM

1409-16

pubmed-meshheading:10098843-Analgesics, Opioid, pubmed-meshheading:10098843-Animals, pubmed-meshheading:10098843-Anions, pubmed-meshheading:10098843-Arachidonic Acid, pubmed-meshheading:10098843-Calcium, pubmed-meshheading:10098843-Chelating Agents, pubmed-meshheading:10098843-Egtazic Acid, pubmed-meshheading:10098843-Endothelin-1, pubmed-meshheading:10098843-Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, pubmed-meshheading:10098843-Enkephalins, pubmed-meshheading:10098843-Enzyme Inhibitors, pubmed-meshheading:10098843-Female, pubmed-meshheading:10098843-G Protein-Coupled Inwardly-Rectifying Potassium Channels, pubmed-meshheading:10098843-GTP-Binding Proteins, pubmed-meshheading:10098843-Gene Expression, pubmed-meshheading:10098843-Ion Channel Gating, pubmed-meshheading:10098843-Oocytes, pubmed-meshheading:10098843-Phospholipases A, pubmed-meshheading:10098843-Phospholipases A2, pubmed-meshheading:10098843-Phosphoprotein Phosphatases, pubmed-meshheading:10098843-Potassium Channels, pubmed-meshheading:10098843-Potassium Channels, Inwardly Rectifying, pubmed-meshheading:10098843-Protein Kinase C, pubmed-meshheading:10098843-Rats, pubmed-meshheading:10098843-Receptor Cross-Talk, pubmed-meshheading:10098843-Receptors, Endothelin, pubmed-meshheading:10098843-Receptors, Muscarinic, pubmed-meshheading:10098843-Receptors, Opioid, mu, pubmed-meshheading:10098843-Staurosporine, pubmed-meshheading:10098843-Xenopus laevis

Activation of the endothelin receptor inhibits the G protein-coupled inwardly rectifying potassium channel by a phospholipase A2-mediated mechanism.

Journal Article, Research Support, U.S. Gov't, P.H.S.