Effects of Quercetin on Human α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor-Mediated Ion Currents

Abstract

Glutamate is one of the major excitatory neurotransmitters in the central nervous system. 1) Glutamate binds to various cation-gated glutamate receptors, which include a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), Nmethyl-D-aspartate (NMDA) and kainate receptors.1,2) Binding of glutamate to AMPA receptors mediates fast synaptic transmissions to induce postsynaptic depolarization and neuronal firing.3) Thus, the activation of AMPA receptors are involved in various physiological functions of the nervous system such as learning and memory. In abnormal conditions, activation of AMPA receptors also induces excitotoxicity in the nervous system. 4,5) AMPA receptors consist of poreforming tetramer subunits GluR1-4, and each subunit can be alternatively spliced into either a flip or flop form. 2,6) GluR1-4 are three homologous transmembrane proteins that bind extracellular glutamate, which forms the receptor's cation channel. On the other hand, mammalian AMPA receptors require TARP (transmembrane AMPA receptor regulatory proteins) auxiliary subunits.7) The prototypical TARP, stargazin, is mutated in stargazer mice that suffer from absence epilepsy and cerebellar ataxia. 8) Stargazin is a four transmembrane protein and plays a important role in AMPA receptor trafficking and channel gating. 9,10) Flavonoids are representative secondary metabolites and substances of low molecular weight found widely in fruits and vegetables. 11) They support various effects in the nervous system including analgesia, motility and sleep, anticonvulsant, sedative and anxiolytic effects. [12][13][14] A line of evidence supports that flavonoids including quercetin exhibit in vitro and in vivo neuroprotective effects.15,16) Related with ligandgated ion channel regulations, recent reports have demonstrated that quercetin regulates the Cys-loop family of ligand-gated anion and cation channels such as g-aminobutyric acid A (GABA A ) and GABA C , glycine, and 5-HT 3A receptors expressed in Xenopus laevis oocytes. [17][18][19][20] Although AMPA receptor is not a Cys-loop family receptor, it does play an important role in the nervous system physiologically or pathologically as one of the ligand-gated ion channels. 1,2) However, it is not clear whether AMPA receptor is involved in quercetin action and relatively little is known regarding how quercetin promotes its effect on AMPA receptor channel activity.In this study, we investigated the effects of quercetin on the AMPA channel activity regulation expressed in Xenopus oocytes. For this study, we first expressed human AMPA receptor by co-injection of cRNAs of GluR1 and auxiliary subunit, stargazin in Xenopus oocytes and examined the effect of quercetin on glutamate-induced inward current (I Glu ). We used this system because: (1) Xenopus laevis oocytes have been widely used as a tool to express the membrane proteins encoded by exogenously administered cDNAs or cRNAs including receptors, ion channels, and transporters 21) ; and (2) AMPA receptor channels expressed in Xenopus oocytes by the...

Flavonoids as positive allosteric modulators of α7 nicotinic receptors

“…showing a positive effect only on 7 and an inhibitory effect on most neurotransmitter receptors, including GABA-, serotonin-, ACh-, glycine-and glutamate-activated receptors (Goutman et al, 2003;Grønlien et al, 2007;Huang et al, 1999;Huang and Dillon, 2000;Lee et al, 2011aLee et al, , 2011cLee et al, , 2011bLee et al, , 2008Lee et al, , 2007Lee et al, , 2005Shin et al, 2010).…”

“…Moreover, in vivo beneficial effects of flavonoids take place at lower doses than those required for their direct antioxidant activity, indicating that additional mechanisms involving signalling processes may be implicated in their actions (Dajas et al, 2013;Flanagan et al, 2018;Spencer et al, 2012;Williams et al, 2004). Among these processes, flavonoids have been shown to directly modulate neurotransmitter receptors and ion channels (Goutman et al, 2003;Hanrahan et al, 2011;Huang et al, 1999;Huang and Dillon, 2000;Johnston, 2015;Lee et al, 2007Lee et al, , 2005Shin et al, 2010).…”