Leukotriene C4 modulation of muscarinic K+ current activation in bullfrog atrial myocytes.
The effects of leukotriene C4 (LTC4) on activation of muscarinic acetylcholine receptor (mAChR)-stimulated, inwardly rectifying K+ current (IK[ACh]) were examined in single bullfrog atrial myocytes using the whole-cell patch clamp technique. LTC4 produced a reversible, concentration-dependent increase in steady-state, guanosine-gamma-thiotriphosphate (GTP gamma S)-activated IK[ACh], with a K0.5 of 3.1 microM. LTC4 also increased the rate of GTP gamma S-mediated IK[ACh] activation, both in the absence and presence of 1 nM ACh, with comparable K0.5 values of 4.7 microM under basal conditions and 4.9 microM in the presence of 1 nM ACh. LTC4 did not alter the relative affinities of the G protein, Gk, for GTP gamma S and GTP. We hypothesize that all of the effects of LTC4 on the kinetics of Gk-mediated IK[ACh] activation are produced at a common site with a K0.5 of 3-5 microM. The effects of LTC4 on IK[ACh] activation are fully reversible in the presence of GTP gamma S. Under physiological conditions (i.e., intracellular GTP), 10 microM LTC4 increased the ACh-activated peak IK[ACh]. Inhibitors of cellular LTC4 production, including 5,8,11,14-eicosatetraynoic acid, baicalein, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, and alpha-pentyl-4-(2-quinolinylmethoxy)-benzene methanol, greatly attenuated ACh-dependent IK[ACh] activation, preventing activation of peak, and producing a lower steady-state IK[ACh] (when compared with the control response in the same cell). Addition of exogenous LTC4 was able to overcome the effects of LTC4 synthesis inhibitors, restoring both the peak and steady-state IK[ACh] responses. Although the mechanism of LTC4-mediated modulation of IK[ACh] activation is not known, our results suggest that endogenously produced lipoxygenase metabolites of arachidonic acid, specifically LTC4, are involved in the physiological process of IK[ACh] activation.
Scherer
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RW
Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205.
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Breitwieser
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D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011892:Rana catesbeiana; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D013189:SRS-A; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D000110:Acetylcholinesterase; D019204:GTP-Binding Proteins; D000109:Acetylcholine