Article Dans Une Revue FASEB Journal Année : 2009

Discovery of a functional immunoreceptor tyrosinebased switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis

Résumé

The orexin neuropeptides promote ro-reward systems (5) or drug addiction (6, 7). Functions of orexins have also been described in peripheral tissues (8, 9), including digestive tract, gonads, and adrenal glands. The central and peripheral actions of orexins are mediated by two 7-pass transmembrane receptors, orexin receptors type 1 and 2 (OX1R and OX2R), that recognize both orexins with poor selectivity (1). The activation of orexin receptors induces cellular calcium transients through coupling to G q heterotrimeric proteins (10). The OX1R has also been shown to be linked to calcium influx through a signal pathway independent of G q activation (11).

A totally unexpected aspect of orexins has emerged recently, when it was shown that orexins induce dramatic apoptosis resulting in massive reduction of cell growth in a set of tumor cell lines including human colon cancer cells (12), human neuroblastoma cells (12), and rat pancreatic tumor cells (13). The cellular mechanism whereby orexins drive apoptosis involves mitochondrial cytochrome c release into cytosol and activation of caspase-3 and caspase-7 (12). The orexindriven apoptosis is mediated by OX1R in colon cancer and neuroblastoma cells (12) and by OX2R in pancreatic tumor cells (13). We have previously demonstrated that the expression of recombinant OX1R or OX2R in Chinese hamster ovary (CHO) cells is sufficient to confer the ability of orexins to promote apoptosis, showing that it is an intrinsic property of orexin receptors (13, 14).

Because the classic G q -mediated Ca 2ϩ response was certainly not sufficient to explain the orexin receptormediated apoptotic effects of orexins, we previously speculated that the apoptotic action of orexins might be driven by an original mechanism not yet identified in 7-pass transmembrane G protein-coupled receptors (GPCRs) (14). This questioning led us to show that a tyrosine-based inhibitory motif (ITIM), which is usually considered as a hallmark of immunoreceptors (15), is

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Dates et versions

hal-05452300 , version 1 (24-02-2026)

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Aadil El Firar, Thierry Voisin, Christiane Rouyer-Fessard, Mariano A. Ostuni, Alain Couvineau, et al.. Discovery of a functional immunoreceptor tyrosinebased switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis. FASEB Journal, 2009, 23 (12), pp.4069-4080. ⟨10.1096/fj.09-131367⟩. ⟨hal-05452300⟩

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