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  • In some pancreatic and non

    2019-11-26

    In some pancreatic and non-pancreatic tissues, the chloride and calcium channels are heavily regulated by phosphorylation by protein kinases, such as PKC, cyclic AMP-dependent protein kinase (PKA), PKCaMKII, PI3K and protein tyrosine kinases [7,36,37]. Since the interaction of triterpenes with receptors linked to insulin secretion, such as Takeda-G-protein-receptor-5 (TGR5) (observed for BA [38]), as well as glucose-mediated signaling in islets may lead to the activation of protein kinases that potentiate and sustain insulin secretion after cell repolarization [39], the participation of PKC was investigated. Together with the initial steps, the potentiation of the end processes (translocation and vesicular fusion) are key to insulin secretion and to a rapid response to postprandial glycemic elevations, guaranteeing effective protection of insulin-independent tissues against glycemic peaks [40]. As such, the involvement of PKC (Fig. 4) in stimulatory BA induced-calcium influx shows that this triterpene may be regulating insulin secretion broadly, acting at different targets simultaneously since it did not alter the glucose uptake (Fig. 5), as supported by its strong and rapid reduction of glycemia in hyperglycemic animals. This is the first description of the PKC-dependent action of BA in pancreatic islets, although other triterpenes have been previously reported to exert effects via this mechanism in islets, such as 3β-hydroxyhop-22 (29) -ene [18], and in skeletal muscle in pathways related to GLUT4 translocation, such as ursolic Kifunensine synthesis [41]. All these effects are corroborated by the strong increase in static insulin secretion from islets incubated with BA (Fig. 6).
    Conclusions The effect of the BA triterpene on calcium influx depends on the activity of KATP, L-VDCCs, ClCs and CaCCs channels, as well as the PKC enzyme, which explains the potent insulinogenic action of this molecule, ensuring the secretion of insulin and determining its strong antihyperglycemic effect, as schematically represented in Fig. 7. The elucidation of the mechanism of action of BA on insulin secretion is of great pharmacological importance for the therapy of diabetes.
    Introduction Chloride ions (Cl−) are essential micronutrients for higher plants. Cl− plays an important role in a series of cellular events, such as regulating enzyme activities and pH, stabilizing membrane potential, and acting as a co-factor in photosynthesis (Franco-Navarro et al., 2016). Recent studies from the cellular to the whole plant level have revealed that the uptake, transport, and accumulation of Cl− are associated with salt tolerance (S. Wang et al., 2015; Nguyen et al., 2016). NaCl is distributed widely and is known to induce cellular osmotic and ionic stresses (Munns and Tester, 2008). It is known that for most plant species, Na+ ions are toxic to cells at much lower concentrations than Cl− ions. While many studies have focused on Na+ transport (Yamaguchi et al., 2013; Britto and Kronzucker, 2015), research about the transport of Cl− is relatively limited, especially in plants. Four gene families that encode chloride transporters or channels have been reported in Arabidopsis thaliana, including SLAC/SLAH (slow anion channel), ALMT (aluminum-activated malate transporter), CLC (chloride channel), and CCC (cation-chloride cotransporter) (Barbier-Brygoo et al., 2011). For the SLAC/SLAH family, the Arabidopsis genome harbors four homologues of SLAC1, including SLAH1-4. The AtALMT family possesses 14 members divided into four clades. The AtCCC family proteins are suggested to be involved in long-distance Cl− transport. The CCC family is divided into three groups, including K+-Cl− cotransporters (KCC), Na+-Cl− cotransporters (NCC), and Na+-K+-Cl− cotransporters (NKCC). The chloride channel (CLC) protein family is ubiquitous and is present in most organisms, including bacteria, yeast, animals, and plants (Mindell and Maduke, 2001; Matulef and Maduke, 2007; Jentsch, 2008; Barbier-Brygoo et al., 2011). CLC-0, a voltage-gated chloride channel, which was identified in the electric organ of Torpedo fish, was the first characterized member of the CLC protein family (Jentsch et al., 1990). Mammals have nine CLC genes that encode both Cl− channels and Cl−/H+ antiporters. The Cl− channels are expressed at the plasma membrane, Kifunensine synthesis and the Cl−/H+ antiporters are localized to the intracellular compartments (Jentsch et al., 2005). In bacteria, CLCs function as electrogenic chloride/proton antiporters (Dutzler et al., 2002). In plants, the initial CLC genes were cloned in tobacco (CLC-Nt1) (Lurin et al., 1996) and Arabidopsis (AtCLCa) (Geelen et al., 2000). Subsequently, more CLC gene homologues were isolated from Arabidopsis (De Angeli et al., 2006; von der Fecht-Bartenbach et al., 2007), rice (Nakamura et al., 2006), soybean (Wong et al., 2013; Wei et al., 2016), orange (Wei et al., 2013), and maize (S. Wang et al., 2015).