Leukotriene receptors.
The current challenge in research on leukotriene receptors is to clone these molecules. Traditional protein purification approaches have not been successful in providing sequence information. Solubilization of cys-LT1 has been achieved but results in the dissociation of G-proteins and the loss of high affinity binding (Mong et al., 1986b; Mong and Sarau, 1990), while cys-LT2 activity cannot be monitored by other than functional assays and there have not been any purification attempts. Partial purification of B-LT has been reported but has not been continued to homogeneity (Sherman et al., 1992; Votta et al., 1990; Miki et al., 1990). Nor have attempts to clone these receptors through either homology screening or expression cloning been successful. The cloning of the prostanoid receptors, described in detail elsewhere in this volume, has shown that these receptors belong to a distinct family within the G-protein-coupled receptor superfamily. It is probable, therefore, that the leukotriene receptors will also belong to a separate group within this superfamily since phylogenic comparisons have shown that receptors displaying high affinity for structurally related ligands exist as discrete families. Recently, a human cDNA encoding an orphan FMLP-related receptor cloned from HL60 cells of myeloid lineage was identified as the receptor for another eicosanoid, lipoxin A (Fiore et al., 1994). FMLP has a similar profile of biological actions to LTB4. Moreover, LTD4 showed a high degree of cross-reactivity with this receptor with an affinity only 20-fold less that of lipoxin A, although LTB4 was inactive. It remains to be determined whether the leukotriene receptors will fall into this class of receptors. The cloning of the leukotriene receptors will allow identification of the different receptor types and subtypes and potentially splice variants. Evaluation of currently developed antagonists at these receptor types could also open the way for novel therapies for inflammatory conditions.
Metters
K M
KM
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Dorval, Quebec, Canada.
D000345:Affinity Labels; D000818:Animals; D006801:Humans; D020024:Leukotriene Antagonists; D007975:Leukotriene B4 / Q000378:metabolism / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction; D018077:Receptors, Leukotriene / Q000145:classification / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*; D015398:Signal Transduction
D000345:Affinity Labels; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4