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

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

Research output: Contribution to journalArticle

Abstract

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-γ-thiotriphosphate (GTPγS)-activated IK[ACh], with a K0.5 of 3.1 μM. LTC4 also increased the rate of GTPγS-mediated IK[ACh] 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[ACh] activation are produced at a common site with a K0.5 of 3-5 μM. The effects of LTC4 on IK[ACh] 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[ACh]. Inhibitors of cellular LTC4 production, including 5,8,11,14-eicosatetraynoic acid, baicalein, cinnamyl-3,4-dihydroxy-α-cyanocinnamate, and α-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.

Original languageEnglish (US)
Pages (from-to)125-141
Number of pages17
JournalJournal of General Physiology
Volume102
Issue number1
StatePublished - Jul 1993

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Rana catesbeiana
Leukotriene C4
Muscle Cells
Cholinergic Agents
Guanosine
Guanosine Triphosphate
5,8,11,14-Eicosatetraynoic Acid
Arachidonate Lipoxygenases
Physiological Phenomena
Patch-Clamp Techniques
Muscarinic Receptors
Benzene
GTP-Binding Proteins
Methanol

ASJC Scopus subject areas

  • Physiology

Cite this

Leukotriene C4 modulation of muscarinic K+ current activation in bullfrog atrial myocytes. / Scherer, Roberta; Lo, C. Frederick; Breitwieser, Gerda E.

In: Journal of General Physiology, Vol. 102, No. 1, 07.1993, p. 125-141.

Research output: Contribution to journalArticle

Scherer, Roberta ; Lo, C. Frederick ; Breitwieser, Gerda E. / Leukotriene C4 modulation of muscarinic K+ current activation in bullfrog atrial myocytes. In: Journal of General Physiology. 1993 ; Vol. 102, No. 1. pp. 125-141.
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abstract = "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-γ-thiotriphosphate (GTPγS)-activated IK[ACh], with a K0.5 of 3.1 μM. LTC4 also increased the rate of GTPγS-mediated IK[ACh] 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[ACh] activation are produced at a common site with a K0.5 of 3-5 μM. The effects of LTC4 on IK[ACh] 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[ACh]. Inhibitors of cellular LTC4 production, including 5,8,11,14-eicosatetraynoic acid, baicalein, cinnamyl-3,4-dihydroxy-α-cyanocinnamate, and α-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.",
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