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  • In addition to an action

    2019-09-09

    In addition to an action via P2Y receptors, extracellular UDP activates GPCRs for cysteinyl leukotrienes (CysLT1, CysLT2; Mellor et al., 2001, 2003). GPR17 has been reported to function as a receptor for cysteinyl leukotrienes and uracil nucleotides (Boda et al., 2011; Fumagalli et al., 2011; but see Hennen et al., 2013; Qi et al., 2013).
    P2Y receptor structure
    Pharmacology Several subtype selective compounds have been developed in recent years (Jacobson and Müller, 2016; Rafehi and Müller, 2018). These compounds are helpful tools for analyzing the roles of P2Y receptor subtypes in physiology and pathophysiology. The present article summarizes pharmacological properties of the eight human P2Y receptor subtypes and discusses selective compounds.
    Conclusion
    Declaration of conflicting interest
    CysLT1 and CysLT2 receptors are G protein-coupled receptors (GPCRs) that are specific in their binding of cysteinyl leukotrienes (cys-LTs). Several GPCRs are reported to function as homo- or heterodimeric complexes. Our group has previously demonstrated that human mast cells (hMCs) derived in vitro from cord blood express both of these receptor subtypes, but that certain cys-LT-dependent signaling functions (particularly calcium flux and ERK MAP kinase phosphorylation) were completely dependent on CysLT1 receptors. We used specific polyclonal GSK1016790A clinical and immunoprecipitation from hMCs and from neutrophils to determine whether CysLT1 and CysLT2 receptor proteins form heteromeric complexes. CysLT1 and CysLT2 receptors co-precipitate with one another from extracts of both hMCs and peripheral blood neutrophils. This association was specific and did not occur between either cys-LT receptor and other related GPCRs. Neutrophils responded to a partial CysLT2 receptor agonist, BAY-u9773, with a calcium flux that was nearly completely blocked by pre-treatment of the cells with a CysLT1 receptor-selective antagonist, MK571. Collectively, these observations indicate that CysLT1 and CysLT2 receptors function as a heterodimeric complex to mediate cys-LT-dependent proinflammatory functions in hematopoietic effector cells.
    Cysteinyl leukotrienes (CysLTs, including LTC, LTD, and LTE), 5-lipoxygenase metabolites of arachidonic acid, are potent pro-inflammatory mediators , . Their actions are mediated by two G protein-coupled receptors, CysLT and CysLT receptors , . CysLTs modulate at least four responses: vascular and smooth muscle cell function, immune, inflammation, and tissue repair via activating CysLT and CysLT receptors . In peripheral tissues, as an important response, CysLTs induce tissue edema in lung , , liver , nose , heart , and kidney . In the central nervous system, CysLTs induce the disruption of brain-blood barrier (BBB) and brain edema , , , . We have recently reported that CysLT receptor antagonists (pranlukast and montelukast) inhibit BBB disruption and brain edema after focal cerebral ischemia in rats and mice , suggesting that CysLTs might mediate post-ischemic BBB disruption and the resultant brain edema via CysLT receptor. However, the mechanisms have not been clarified. On the other hand, it is well known that aquarorin 4 (AQP4), a member of water channel family (aquaporins), plays a major role in brain water homeostasis and brain edema , , . AQP4 is primarily distributed in astrocyte endfeet surrounding the blood vessels throughout the brain and spinal cord, and in ependymal cells in ventricular surface . In APQ4-deficient mice, the distinct roles of AQP4 have been proven in the two main types of brain edema, cytotoxic and vasogenic edema , . AQP4 deficiency reduces the cytotoxic edema induced by focal cerebral ischemia , , water intoxication , , and bacterial meningitis , but worsens the vasogenic (fluid leak) edema induced by brain tumor , brain abscess , cortical freeze-injury , and hydrocephalus . Since both CysLTs and AQP4 in the brain are increased after focal cerebral ischemia , , it is important to clarify whether CysLTs-induced post-ischemic brain edema is mediated via enhancing AQP4 expression.