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Regulation of intracellular calcium release channel function by arachidonic acid and leukotriene B4
1Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut, 06030-3505, USA. frank.striggow@medizin.uni-magdeburg.de
Abstract:
Arachidonic acid has been shown to affect the intracellular calcium concentration in many cell types (1-5), but the target of this regulation was unclear. Here we show that two types of intracellular calcium release channel, the inositol 1,4,5-trisphosphate-gated channel (IP3R) and the ryanodine receptor (RyR) are modulated in an opposing manner by arachidonic acid and its product leukotriene B4 (LTB4). The IP3R was inhibited by arachidonic acid (Ki = 27 nM), whereas the RyR was unaffected by this compound. In contrast, 100 nM LTB4 fully activated the RyR but did not influence the IP3R. The concerted action of arachidonic acid and LTB4 could provide specific mobilization of stored calcium by terminating IP3-induced release and activating the RyR/calcium release channel by its newly identified agonist.
Insights
Arachidonic acid and leukotriene B4 (LTB4) oppositely regulate intracellular calcium release channels. Arachidonic acid inhibits the inositol 1,4,5-trisphosphate-gated channel (IP3R), while LTB4 activates the ryanodine receptor (RyR).
Area of Science:
- Cellular Biology
- Biochemistry
- Molecular Pharmacology
Background:
- Arachidonic acid is known to influence intracellular calcium levels in various cell types.
- The precise molecular targets responsible for arachidonic acid's regulation of calcium were previously unidentified.
Purpose of the Study:
- To elucidate the specific intracellular calcium release channels modulated by arachidonic acid and its metabolite, leukotriene B4 (LTB4).
- To investigate the opposing effects of arachidonic acid and LTB4 on the inositol 1,4,5-trisphosphate-gated channel (IP3R) and the ryanodine receptor (RyR).
Main Methods:
- Investigated the modulation of IP3R and RyR activity by arachidonic acid and LTB4.
- Determined the inhibitory constant (Ki) for arachidonic acid's effect on IP3R.
Main Results:
- Arachidonic acid demonstrated inhibitory effects on the IP3R with a Ki of 27 nM, while having no significant impact on the RyR.
- Leukotriene B4 (LTB4), at 100 nM, fully activated the RyR but did not affect the IP3R.
- These findings reveal opposing modulatory actions of arachidonic acid and LTB4 on distinct calcium release channels.
Conclusions:
- Arachidonic acid and LTB4 act antagonistically on IP3R and RyR, respectively, to regulate intracellular calcium.
- This coordinated action suggests a mechanism for precise calcium mobilization by terminating IP3-mediated release and activating RyR.