ARACHIDONIC-ACID METABOLITES ALTER G-PROTEIN MEDIATED SIGNAL TRANSDUCTION IN HEART - EFFECTS ON MUSCARINIC K+ CHANNELS

The muscarinic acetylcholine receptor (mAChR)-stimulated, inwardly rectifying K+ current (IK[ACh]) was examined in single bullfrog atrial cells using the whole-cell patch clamp technique. Iir was activated either by bath addition of 1 µM ACh or via activation of the G protein, Gk, with guanosine-γ-thiotriphosphate (GTPγS). Arachidonic acid (AA) modulated IK[ACh] under both conditions. AA decreased mAChR-stimulated IK[ACh] and increased the rate of decay from the peak current (desensitization). In addition, AA affected GTPγS-activated IK[ACh] by modulation of Gk. The effects of AA and its metabolites on Gk were assessed by examining their effects on both the basal rate of Gk activation by GTPγS, and the mAChR-mediated increase in activation rate produced by nanomolar ACh. AA increased the basal rate of GTPγS-mediated IK[ACh] activation, but reduced the ACh-induced augmentation of this rate. All of the effects of AA on GTPγS-mediated IK[ACh] activation were produced by metabolites. A lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), decreased the basal and ACh-enhanced rate of IK[ACh] activation in both the presence and absence of exogenous AA. In contrast, indomethacin (INDO), a cyclooxygenase inhibitor, increased the basal rate of IK[ACh] activation by GTPγS in both the presence and absence of exogenous AA, and reversed the effects of AA on the ACh-augmented basal rate. AA metabolites produced via lipoxygenase and cyclooxygenase pathways thus have opposing effects on the signal transduction pathway from mAChR to IK[ACh]. We directly tested a lipoxygenase pathway metabolite, LTC4, on GTPγS-mediated IK[ACh] activation and found that it not only overcame the inhibitory effects of NDGA, but also increased both the basal and ACh-augmented rate of IK[ACh] activation. From these data, we propose that AA metabolites modulate the function of G k by altering its kinetic properties. © 1990, Rockefeller University Press., All rights reserved.