Flavonoids as positive allosteric modulators of α7 nicotinic receptors

Abstract

The use of positive allosteric modulators (PAM) of α7 nicotinic receptors is a promising therapy for neurodegenerative, inflammatory and cognitive disorders. Flavonoids are polyphenolic compounds showing neuroprotective, anti-inflammatory and pro-cognitive actions. Besides their well-known antioxidant activity, flavonoids trigger intracellular pathways and interact with receptors, including α7. To reveal how the beneficial actions of flavonoids are linked to α7 function, we evaluated the effects of three representative flavonoids-genistein, quercetin and the neoflavonoid 5,7-dihydroxy-4-phenylcoumarinon whole-cell and single-channel currents. All flavonoids increase the maximal currents elicited by acetylcholine with minimal effects on desensitization and do not reactivate desensitized receptors, a behaviour consistent with type I PAMs. At the single-channel level, they increase the duration of the open state and produce activation in longduration episodes with a rank order of efficacy of genistein > quercetin ≥ neoflavonoid. By using mutant and chimeric α7 receptors, we demonstrated that flavonoids share transmembrane structural determinants with other PAMs. The 7-PAM activity of flavonoids results in decreased cell levels of reactive oxygen species. Thus, allosteric potentiation of α7 may be an additional mechanism underlying neuroprotective actions of flavonoids, which may be used as scaffolds for designing new therapeutic agents.

Apigenin and Structurally Related Flavonoids Allosterically Potentiate the Function of Human α7-Nicotinic Acetylcholine Receptors Expressed in SH-EP1 Cells

“…Radioligand binding experiments indicate that apigenin and other flavonoids does not alter [ 125 I] α-bungarotoxin binding suggesting that these compounds act as allosteric modulators of the α7-nACh receptor. These results confirm earlier findings with genistein and quercetin [ 17 , 18 , 19 ], and identify apigenin, and other flavonoids, as likely PAM of the human α7-nACh receptor. The PAMs are promising therapeutic agents since they maintain the temporal and spatial characteristics of the endogenous activation of the receptor and are usually more selective than agonists [ 1 ].…”

“…Further studies with more complex phytochemicals identified curcumin and its metabolites as positive allosteric modulators (PAM) of α7 nACh receptor [ 14 , 15 , 16 , 17 ]. Importantly, some of the flavonoid-group phytochemicals, such as genistein and quercetin, were recently shown to act as a PAM of α7 nACh receptor [ 17 , 18 , 19 ]. In the present study, we have investigated the effects of a panel of polyhydroxy flavonoids that are the products of differently substituted 5,7-dihydroxy-4H-chromen-4-one structural skeleton ( Figure 1 ).…”

Tyrosine phosphorylation differentially fine-tunes ionotropic and metabotropic responses of human α7 nicotinic acetylcholine receptor

“…In non-treated cells and in the absence of PP2, channel activity appeared mainly as brief and isolated openings or as several openings in quick succession, known as bursts, which correspond to the activation episode of a single receptor molecule (Fig. 1 a) [ 32 , 38 ]. Open and burst duration histograms were described by two exponential components, with mean durations of the slowest components of 0.32 ± 0.07 ms and 0.48 ± 0.13 ms ( n = 17), respectively (Fig.…”

“…Single channels were recorded in the cell-attached patch configuration [ 32 , 38 ]. The bath and pipette solutions contained 142 mM KCl, 5.4 mM NaCl, 1.8 mM CaCl 2 , 1.7 mM MgCl 2 and 10 mM HEPES (pH 7.4).…”

“…Open-time histograms were fitted by the sum of exponential functions by maximum likelihood using the program TACFit (Bruxton Corporation, Seattle, WA, USA). Bursts of channel openings were identified as a series of closely separated openings preceded and followed by closings longer than a critical duration, which was taken as the point of intersection between closed components as previously described [ 32 , 34 , 38 ]. Typically, critical durations were defined by the intersection between the first and second briefest components in the closed-time histogram for bursts of α7 (~ 200–400 µs).…”