Abstract
5-Oxo-eicosatetraenoic acid (5-oxoETE) stimulated human neutrophil (PMN) and eosinophil chemotaxis, PMN hexose uptake, and PMN membrane GTP/GDP exchange. Pertussis toxin (PT), a blocker of heterotrimeric G proteins (GP), completely inhibited these responses, but proved far less effective on the same responses when elicited by leukotriene B4, C5a, FMLP, platelet-activating factor, IL-8, or RANTES chemotactic factors. 5-OxoETE also specifically bound to the membrane preparations that conducted GTP/GDP exchange. This binding was down-regulated by GTPgammaS, but not ADPgammaS, and displaced by 5-oxoETE analogues, but not by leukotriene B4, lipoxin A4, or lipoxin B4. Finally, PMN expressed PT-sensitive GP alphaiota2 and PT-resistant GP alphaq/11- and alpha13-chains; eosinophils expressed only alphai2 and alphaq/11. We conclude that 5-oxoETE activates granulocytes through a unique receptor that couples preferentially to PT-sensitive GP. The strict dependency of this putative receptor on PT-sensitive GP may underlie the limited actions of 5-oxoETE, compared with other CF, and help clarify the complex relations between receptors, GP, cell signals, and cell responses.
Highlights
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polymorphonuclear neutrophils (PMN) incubated with [14C]DOG progressively took up radioactivity for Ͼ1.5 h, and various agents induced an increase in this uptake
Pertussis toxin (PT) blocked the actions of chemotactic factors (CF), but did not alter hexose uptake in resting cells nor inhibit agents that operate independently of G proteins (GP) viz, PMA, ionomycin, or TNF-␣ (Fig. 2)
Summary
5-oxo-ETE, 5-oxo-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoate; CF, chemotactic factor; [14C]DOG, D-[14C]-2-deoxyglucose; ECL, enhanced chemiluminescence; Eo, eosinophil; GP, heterotrimeric G protein; GPCR, G protein-coupled receptor; 15-HETE, 15(S)-hydroxy-5,8,12,14-(Z,Z,Z,E)-eicosatetraenoate; LTB4, leukotriene B4; LXA4, lipoxin A4; LXB4, lipoxin B4; MAPK, mitogen-activated protein kinase; 5-oxo-15-hydroxy-ETE, 5-oxo-15(S)-hydroxy-6,8,11,14(E,Z,Z,E)-eicosatetraenoate; PAF, platelet-activating factor; PMN, polymorphonuclear neutrophil; PT, pertussis toxin; rac-5-HETE, 5-(rac)-hydroxy-6,8,11,14-(E,Z,Z,Z)eicosatetraenoate. GPCR can elicit different responses in the same cell by linking to different GP subfamilies [16, 17]. Based on their sensitivity to the Gi ␣-chain inhibitor, PT, GPCR for CF couple to Gi [18, 19]. Transfected C5a [20], IL-8 [21], and LTB4 [23] receptors must couple to ␣16-, but do not or cannot couple to ␣q- or ␣11-chains to elicit various responses. 5-oxoETE analogues act preferentially on and through PT-sensitive GP, and this preference may explain their limited actions
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