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

Abstract

The effects of leukotriene C4 (LTC4) on activation of muscarinic acetylcholine receptor (mAChR)-stimulated, inwardly rectifying K + current (I~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--y-thiotriphosphate (GTP~tS)-activated IKt^Chl, with a K0.5 of 3.1 IzM. LTC4 also increased the rate of GTP~/S-mediated IKIAChl activation, both in the absence and presence of 1 nM ACh, with comparable K0.5 values of 4.7 izM under basal conditions and 4.9 IzM in the presence of 1 nM ACh. LTC4 did not alter the relative affinities of the G protein, Gk, for GTP~/S and GTP. We hypothesize that all of the effects of LTC4 on the kinetics of Gk-mediated IKtACh] activation are produced at a common site with a K0.5 of 3-5 I~M. The effects of LTC4 on IKtACh] activation are fully reversible in the presence of GTP,IS. Under physiological conditions (i.e., intracellular GTP), 10 izM LTC4 increased the ACh-activated peak Ir4AChl. Inhibitors of cellular LTC4 production, including 5,8,11,14-eicosatetraynoic acid, baicalein, cinnamyl-3,47dihydroxy-a-cyanocinnamate , and a-pentyl-4-(2-quinolinylmethoxy)-benzene methanol, greatly attenuated ACh-dependent IrqAChl activation, preventing activation of peak, and producing a lower steady-state IKIAChl (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 Iv4AChl responses. Although the mechanism of LTC4-mediated modulation of IKtACnl activation is not known, our results suggest that endogenously produced lipoxygenase metabolites of arachidonic acid, specifically LTC4, are involved in the physiological process of I~lAChl activation.

Modulation of calcium channel currents by arachidonic acid in single smooth muscle cells from vas deferens of the guinea‐pig

“…K channels coupled to muscarinic receptors in cardiac myocytes (Kurachi et al, 1989;Kim et al, 1989;Scherer et al, 1993) and M channels in hippocampal neurones (Schweitzer et al, 1990) are activated by AA via leukotriene production. It has been reported that PGE2 can reduce Ca channel currents in rat sympathetic neuronal cells (Ikeda, 1992).…”

Biological Properties of Baicalein in Cardiovascular System

“…Lipoxygenase metabolites of arachidonic acid, specifically leukotriene C4 is involved in the physiological process of activation of muscarinic K + current in bullfrog atrial myocytes and baicalein attenuates acetylcholine-dependent K + channel activation in the cardiomyocytes [60]. However, the clinical relevance of this pharmacological effect needs further assessment.…”

I K.ACh activation by arachidonic acid occurs via a G-protein-independent pathway mediated by the GIRK1 subunit

“…Calculated mean values ±standard error of mean value areshown; number of experiments is specified in parentheses. The difference between the two experimental groups is statistically not significant action has never been fully elucidated [12,21]. Several facts presented here indicate that, rather than G β/γ , the channel subunit itself is the target for AA action:…”