Leukotriene C4 modulation of muscarinic K+ current activation in bullfrog atrial myocytes

Roberta W. Scherer, C. Frederick Lo, Gerda E. Breitwieser

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The effects of leukotriene C4 (LTC4) on activation of muscarinic acetylcholine receptor (mAChR)-stimulated, inwardly rectifying K+ current (IK[Achl]) 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-γ-thiotriphosphate (GTPγtS)-activated IK[Achl] with a K0.5 of 3.1 µM. LTC4 also increased the rate of GTPγS-mediated IK[Achl] activation, both in the absence and presence of 1 nM ACh, with comparable K0.5 values of 4.7 µM under basal conditions and 4.9 µM in the presence of 1 nM ACh. LTC4 did not alter the relative affinities of the G protein, Gk, for GTPγS and GTP. We hypothesize that all of the effects of LTC4 on the kinetics of GK-mediated IK[Achl] activation are produced at a common site with a K0.5 of 3-5 µM. The effects of LTC4 on IK[Achl] activation are fully reversible in the presence of GTPγS. Under physiological conditions (i.e., intracellular GTP), 10 µM LTC4 increased the ACh-activated peak IK[Achl]. Inhibitors of cellular LTC4 production, including 5,8,11,14-eicosatetraynoic acid, baicalein, cinnamyl-3,47dihydroxy-α-cyanocinnamate, and α-pentyl-4-(2-quinolinylmethoxy)-benzene methanol, greatly attenuated ACh-dependent IK[Achl] activation, preventing activation of peak, and producing a lower steady-state IK[Achl] (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[Achl] responses. Although the mechanism of LTC4-mediated modulation of IK[Achl] 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[Achl] activation.

Original languageEnglish (US)
Pages (from-to)125-141
Number of pages17
JournalJournal of General Physiology
Issue number1
StatePublished - Jul 1 1993

ASJC Scopus subject areas

  • Physiology


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