The insulin-releasing agent quercetin-3-oleate stimulates CaV1.2 channels similarly to quercetin, though with a reduced vasorelaxant activity

Abstract

The synthetic derivative quercetin-3-oleate (AV2), a partial agonist of the G-protein-coupled receptor 40 (GPR40), and its parent compound quercetin, a stimulator of Ca_V1.2 channels, promote insulin secretion from INS-1 pancreatic β cells. An in vitro and in silico approach was pursued to assess whether the incorporation of oleic acid at the C3 position maintains quercetin stimulation of Ca_V1.2 channels (key to triggering insulin release) while reducing its vasorelaxant properties. In rat tail main artery myocytes, AV2, like quercetin, stimulated Ba²⁺ currents via Ca_V1.2 channels (I_Ba1.2), demonstrating favourable interaction in molecular docking analyses and molecular dynamics simulations. Although AV2 also stimulated K⁺ currents via K_Ca1.1 channels (I_KCa1.1), its vasorelaxant effect in vascular rings was significantly lower than that of quercetin. AV2 exhibited a positive inotropic effect and increased the frequency of Langendorff-perfused isolated rat hearts, albeit at concentrations one order of magnitude higher than those required for significant I_Ba1.2 stimulation. In in vitro settings, AV2 maintained a significant H₂O₂-induced radical scavenging activity. In conclusion, the conjugation of oleic acid with the dietary flavonoid quercetin in AV2 attenuated its spasmolytic effects on vascular smooth muscle, without affecting its I_Ba1.2 stimulatory activity. This, along with its GPR40 activation, highlights AV2 as a bifunctional agent with the potential to improve selective insulin secretion with minimal vascular effect.

Keywords: Ca(V)1.2 channel; Cardiovascular activity; K(Ca)1.1 channel; Oleic acid; Quercetin.