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    • One study has demonstrated that PUFA reduced both cholestero

    2024-03-25

    One study has demonstrated that ω-3 PUFA reduced both cholesterol and caveolin-1 (a marker of raft), thereby displacing raft-associated signaling molecules from lipid raft [36]. Additionally, DHA treatment decreased the amount of lipid raft in the cell surface and displaced several lipid raft-associated proteins from the raft fraction, and could be partially reversed by adding cholesterol [37]. In the present study, it was unexpectedly found that chronic DHA treatment did not affect the content of caveolin-1, but instead increased the lipid raft levels of C6 cell. This result is consistent with a previous study that demonstrated that DHA treatment increased the size of lipid rafts and membrane order of Ranolazine [40]. Moreover, recent data found that ω-3 PUFA promoted the formation of lipid rafts and inhibited the localization of signaling protein at the immunologic synapse [41]. These findings observed by either us or others are contradictory to those reported previously [42]. That study indicated that DHA treatment disrupted lipid raft. The different effects of DHA on lipid raft among these studies may be due to the different cell types used or different treatment conditions applied. Our results evidently support that the reduced localization of Gsα in lipid raft domains induced by chronic DHA treatment was not due to the disruption of lipid raft (Fig. 4). It has been demonstrated that some specific membrane components may sequester Gsα in lipid raft domains, thereby making them less available to the adenylate cyclase, Gsα effector enzyme [23]. Because lipid raft is also characterized by its enriched cytoskeletal association, it has been hypothesized that cytoskeleton is implicated in the localization of Gsα in lipid raft domains. This hypothesis was supported by a study that demonstrated that the intact cytoskeleton suppressed the Gsα–adenylate cyclase signaling pathway by interacting with signaling components in lipid raft fractions [43]. Another possibility is that caveolin-1 may sequester Gsα in lipid rafts, which is modified by DHA treatment. In this present study, we did not investigate those mechanism and further studies are needed to confirm these two possibilities.
    Conclusions
    Introduction Cyclic AMP, a universal second messenger, which is used by diverse organisms to control processes ranging from chemotaxis to cell differentiation and apoptosis [1]. In mammals, cAMP is synthesized from ATP by two different types of adenylate cyclases (ACs) those are membrane bound and soluble ACs. Adenylate cyclases are mainly regulated through binding of extracellular ligands to GPCRs (G-protein-coupled receptors), pH, bicarbonate and calcium [2], [3], [4]. In addition, a globin-coupled heme containing AC has been described in trypanosomatid parasite Leishmania major (HemAC-Lm) [5]. Like other globin-coupled oxygen sensors [6] (HemAT-Bs [7], AvGReg [8], BpeGReg [9], HemDGC [10], and YddV [11], [12], [13]), the catalytic activity of soluble HemAC-Lm is significantly enhanced by the binding of O2 to the heme iron [5]. Gene knockdown studies suggest that the O2 dependent cAMP signaling via protein kinase A plays a key role in cell survival through the suppression of oxidative stress under hypoxia. Inhibitor of soluble AC (KH7) as well as activator of membrane bound AC (forskolin) is insensitive to this parasite specific AC activity suggesting that the HemAC-Lm appears to be biochemically different from human host ACs. On the basis of primary structure of HemAC-Lm, it is composed of two distinct types of domains: one that binds to ATP (adenylate cyclase domain) at the C-terminal and the other that binds to heme (globin domain) at the N-terminal. O2 binds directly to the distal site of the Ranolazine ferrous form of heme iron by the displacement of the distal site axial ligand and stimulates AC activity [14]. The displacement of the distal site axial ligand by O2 in the globin domain may involve dynamic conformational changes in which the AC domain switches from inactive state to active state. Many studies have revealed that the gaseous ligands such as O2, CO, or NO binding causes a conformational change in the environment of heme that regulates the activity of diverse proteins including soluble guanylate cyclase [15], FixL [16], CooA [17], HemAT [18], AxPDEA1 [19], NPAS2 [20], EcDOS [21], DosC [12], and diguanylate cyclase [11]. We have recently shown that the heme-free form as well as the ferric form of wild type of HemAC-Lm has low AC activity [14]. In contrast to hemoglobin/myoglobin, a key feature of HemAC-Lm is its six-coordinate heme structure in the ferrous states, with the proximal histidine (His161) and an endogenous distal unknown residue. Additionally, HemAC-Lm enzymes have another ∼150 amino acids containing globin like domain (210–360 amino acids) at the middle position between the globin (globin-A) and the AC domains (Fig. 1). However, the detailed functions of the second globin like domain (globin-B) in the HemAC-Lm have not been studied.