Multiple Effects of Echinochrome A on Selected Ion Channels Implicated in Skin Physiology

Abstract

Echinochrome A (Ech A), a naphthoquinoid pigment from sea urchins, is known to have anti-inflammatory and analgesic effects that have been suggested to be mediated by antioxidant activity and intracellular signaling modulation. In addition to these mechanisms, the ion channels in keratinocytes, immune cells, and nociceptive neurons may be the target for the pharmacological effects. Here, using the patch clamp technique, we investigated the effects of Ech A on the Ca2+-permeable TRPV3, TRPV1 and Orai1 channels and the two-pore domain K+ (K2P) channels (TREK/TRAAK, TASK-1, and TRESK) overexpressed in HEK 293 cells. Ech A inhibited both the TRPV3 and Orai1 currents, with IC50 levels of 2.1 and 2.4 μM, respectively. The capsaicin-activated TRPV1 current was slightly augmented by Ech A. Ech A alone did not change the amplitude of the TREK-2 current (ITREK2), but pretreatments with Ech A markedly facilitated ITREK2 activation by 2-APB, arachidonic acid (AA), and acidic extracellular pH (pHe). Similar facilitation effects of Ech A on TREK-1 and TRAAK were observed when they were stimulated with 2-APB and AA, respectively. On the contrary, Ech A did not affect the TRESK and TASK-1 currents. Interestingly, the ITREK2 maximally activated by the combined application of 2-APB and Ech A was not inhibited by norfluoxetine but was still completely inhibited by ruthenium red. The selective loss of sensitivity to norfluoxetine suggested an altered molecular conformation of TREK-2 by Ech A. We conclude that the Ech A-induced inhibition of the Ca2+-permeable cation channels and the facilitation of the TREK/TRAAK K2P channels may underlie the analgesic and anti-inflammatory effects of Ech A.

TRPV3 Ion Channel: From Gene to Pharmacology

“…The compound inhibited rTRPV1, mTRPV2, and hTRPV3, but had no activity to rTRPA1 [68]. Echinochrome A, a naphthoquinoid pigment from sea urchins, inhibited TRPV3 and Orai1 channels in a low micromolar range and modulated two-pore K+ channels [72].…”

Multi‐omic analysis reveals genes and proteins integral to bioactivity of Echinochrome A isolated from the waste stream of the sea urchin industry in Aotearoa New Zealand

“…Echinochrome A (Ech A; 6‐ethyl‐2,3,5,7,8,‐pentahydroxy‐1,4‐naphthoquinone; Figure 1b ) is a bioactive compound extracted from the shells and spines of sea urchins (Hou et al., 2019 ). Ech A has exhibited in vitro and in vivo bioactivity in multiple tissues including kidney (Cui et al., 2022 ), skin (Choi et al., 2022 ; Kim et al., 2023 ; Seol et al., 2021 ; Yun et al., 2021 ), heart (Artyukov et al., 2020 ; Jeong, Kim, Song, Lee, et al., 2014 ; Kim et al., 2015 ; Song et al., 2022 ; Tang et al., 2023 ), bone (Hou et al., 2020 ), lung (Lebed'ko et al., 2015 ; Seo et al., 2015 ) and eyes (Lennikov et al., 2014 ). These results may help explain the therapeutic efficacy of Ech A, perhaps via the antioxidant, anti‐inflammatory and metal‐chelating activities, against several common ailments and diseases (e.g., diabetes (Mohamed et al., 2016 ; Pham et al., 2023 ), ischemia/stroke (Kim et al., 2019 ; Sedova et al., 2015 ), viral infections (Fedoreyev et al., 2018 ; Mishchenko et al., 2020 ), bacterial infections (Sadek et al., 2021 ), inflammation (Park et al., 2021 ; Rubilar et al., 2021 ; Sadek et al., 2021 ), cancer (Lazarev et al., 2016 ; Mohamed, 2021 ) and neurodegenerative diseases (Ekimova et al., 2018 ; Lee, Pronto, et al., 2014 )).…”