Resveratrol inhibits K_v2.2 currents through the estrogen receptor GPR30-mediated PKC pathway

Abstract

Resveratrol (REV) is a naturally occurring phytoalexin that inhibits neuronal K⁺ channels; however, the molecular mechanisms behind the effects of REV and the relevant α-subunit are not well defined. With the use of patch-clamp technique, cultured cerebellar granule cells, and HEK-293 cells transfected with the K(v)2.1 and K(v)2.2 α-subunits, we investigated the effect of REV on K(v)2.1 and K(v)2.2 α-subunits. Our data demonstrated that REV significantly suppressed Kv2.2 but not Kv2.1 currents with a fast, reversible, and mildly concentration-dependent manner and shifted the activation or inactivation curve of Kv2.2 channels. Activating or inhibiting the cAMP/PKA pathway did not abolish the inhibition of K(v)2.2 current by REV. In contrast, activation of PKC with phorbol 12-myristate 13-acetate mimicked the inhibitory effect of REV on K(v)2.2 by modifying the activation or inactivation properties of Kv2.2 channels and eliminated any further inhibition by REV. PKC and PKC-α inhibitor completely eliminated the REV-induced inhibition of K(v)2.2. Moreover, the effect of REV on K(v)2.2 was reduced by preincubation with antagonists of GPR30 receptor and shRNA for GPR30 receptor. Western blotting results indicated that the levels of PKC-α and PKC-β were significantly increased in response to REV application. Our data reveal, for the first time, that REV inhibited K(v)2.2 currents through PKC-dependent pathways and a nongenomic action of the oestrogen receptor GPR30.

Oxidative/antioxidative enzyme-mediated antiproliferative and proapoptotic effects of the GPER1 agonist G-1 on lung cancer cells

“…SOD catalyzes the conversion of superoxide molecules into H 2 O 2 and molecular (38). Thus far, the role of NO in tumor biology has not been elucidated; however, it has been hypothesized that NO plays a role in various physiological and pathophysiological processes, including vasodilation, nerve conduction, immune system processes and cancer (39).…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…In addition, GPER activates eNOS to produce nitric oxide within the vasculature (Meyer et al, 2012a;Lindsey et al, 2014) and sphingosine kinase to yield sphingosine 1-phosphate in cancer cells (Sukocheva et al, 2006). Additional studies have revealed GPER-mediated calcium mobilization (Revankar et al, 2005;Haas et al, 2009) and the regulation of potassium channels (Yu et al, 2011;Dong et al, 2013). In addition to, and as a consequence of, these rapid signaling events, GPER also regulates gene expression, although not to the same extent as ERa (Prossnitz and Maggiolini, 2009a).…”

“…Resveratrol is a phenolic stilbene derivative that inhibited neuronal potassium channels, and this response was reduced by the GPER antagonist G15 or by short hairpin RNAmediated knockdown of GPER (Dong et al, 2013). The simple phenylethanoid hydroxytyrosol and the glycosylated elenolic acid conjugate oleuropein are isolated from olives and have been reported to act as GPER agonists (Chimento et al, 2014a).…”

Estrogen biology: New insights into GPER function and clinical opportunities

“…Many synthetic compounds from the pesticide and plastics industries known to have estrogenic effects have also been demonstrated to bind and/or activate GPER, including atrazine (Albanito et al, 2008), bisphenol A (Dong et al, 2011; Chevalier et al, 2012; Pupo et al, 2012; Sheng et al, 2013), daidzein (Kajta et al, 2013), zearalonone, nonphenol, kepone, p,p’-DDT, o,p’-DDE and 2,2′,5′,-PCB-4-OH (Thomas and Dong, 2006). Finally, a number of phytoestrogens display agonist activity towards GPER, including genistein (Maggiolini et al, 2004; Thomas and Dong, 2006; Vivacqua et al, 2006a), quercetin (Maggiolini et al, 2004), equol (Rowlands et al, 2011), resveratrol (Dong et al, 2013), oleuropein, and hydroxytyrosol (Chimento et al, 2013). …”