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Activation of the Endothelin Receptor Inhibits the G Protein‐Coupled Inwardly Rectifying Potassium Channel by a Phospholipase A 2 ‐Mediated Mechanism
Author(s) -
Rogalski Sherri L.,
Cyr Curt,
Chavkin Charles
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.721409.x
Subject(s) - phospholipase c , potassium channel , chemistry , receptor , protein kinase c , endothelin receptor , microbiology and biotechnology , biophysics , biology , signal transduction , medicine , biochemistry
Abstract: To develop a malleable system to model the well‐described, physiological interactions between G q/11 ‐coupled receptor and G i/o ‐coupled receptor signaling, we coexpressed the endothelin A receptor, the μ‐opioid receptor, and the G protein‐coupled inwardly rectifying potassium channel (Kir 3) heteromultimers in Xenopus laevis oocytes. Activation of the G i/o ‐coupled μ‐opioid receptor strongly increased Kir 3 channel current, whereas activation of the G q/11 ‐coupled endothelin A receptor inhibited the Kir 3 response evoked by μ‐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 apioid receptor. The endothelin‐1‐mediated inhibition was mimicked by arachidonic acid and blocked by the phospholipase A 2 inhibitor arachidonoyl trifluoromethyl ketone. Consistent with a possible phospholipase A 2 ‐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 G q/11 ‐coupled receptor activation may interfere with G i/o ‐coupled receptor signaling by the activation of phospholipase A 2 and subsequent inhibition of effector function by a direct effect of an eicosanoid on the channel.