Potential independent action of sigma receptor ligands through inhibition of the Kv2.1 channel

Abstract

The sigma-1 receptor (σ1-R) and sigma-2 receptor (σ2-R) are potential drug targets for treatment of cancer, pain, depression, retinal degeneration and other neuronal diseases. Previous reports show that sigma-1 receptor modulates the activities of multiple channels. We are interested in possible sigma receptor modulation of Kv2.1, a K+ channel abundant in retinal photoreceptors. We tested the effect of established sigma receptor ligands on Kv2.1 channels which were stably expressed in HEK293 cells. Surprisingly, σ1-R antagonists inhibited Kv2.1 currents in both wild type and σ1-R knockout HEK293 cells that we engineered using the CRISPR/Cas9 technology. Moreover, PB28, a σ1-R antagonist and also σ2-R agonist, inhibited Kv2.1 in σ1-R knockout cells, but this action was not blocked by the σ2-R antagonists that did not have an effect on Kv2.1. We also observed inhibition of electroretinogram by PB28 in wild type as well as σ1-R knockout mice. Thus, the results in this study indicate that the Kv2.1-inhibiting function of the sigma ligands is not sigma receptor dependent, suggesting a direct effect of these ligands on the Kv2.1 channel.

The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

“…D, orange; P = 0.037; n = 5) also in agreement with recent work (Liu et al. ). Bath application of SKF resulted in a ~25% decrease in current amplitude (Fig.…”

“…When the Sig-1R agonists were added to cells transfected with Sig-1R-YFP and Kv2.1, bath application of PRE-084 decreased Kv2.1 currents by 19 AE 8.2% (Fig. 2D, orange; P = 0.037; n = 5) also in agreement with recent work (Liu et al 2017). Bath application of SKF resulted in a~25% decrease in current amplitude ( Fig.…”

“…In this work, we show that Sig-1R activation by SKF inhibits Kv1.2, as observed for other Kv1.x subtypes (Aydar et al 2002;Kinoshita et al 2012;Kourrich et al 2013). This is likely due to Sig-1R activation rather than a direct effect of the ligand on the channel (Lamy et al 2010;Liu et al 2017) Figure 9. Expression of Sig-1R-E102Q abolishes the effect of SKF on Kv1.2 current amplitude and decouples the relationship between slow s act and "high" V 1/2 of Kv1.2 channels in the "slow" gating mode.…”

Is the sigma-1 receptor a potential pharmacological target for cardiac pathologies? A systematic review

“…A total of 13 criteria were assessed, based on the quality checklist formulated by The Checklist of Review Criteria established by the Task Force of Academic Medicine and the GEA-RIME Committee [22] was used. 22 out of 23 papers met at least 12 out of 13 criteria and were included in the study.PaperProblem statement, conceptual framework, and research questionReference to the literature and documentationRelevanceResearch designInstrumentation, data collection, and quality controlPopulation and sampleData analysis and statisticsReporting of statistical analysesPresentation of resultsDiscussion and conclusion: interpretationTitle, authors and abstractPresentation and documentationScientific conductTotal criterla metGao et al , 2018 [59]✓✓✓✓✓✓✓✓✓✓✓✓✓13Qin et al, 2018 [60]✓✓✓✓✓✓✓✓✓✓✓11Liu et al , 2017 [61]✓✓✓✓✓✓✓✓✓✓✓✓12Alam et al , 2017 [49]✓✓✓✓✓✓✓✓✓✓✓✓12Bao et al , 2017 [62]✓✓✓✓✓✓✓✓✓✓✓✓✓13Shinoda et al , 2016 [27]✓✓✓✓✓✓✓✓✓✓✓✓12Stracina et al , 2015 [63]✓✓✓✓✓✓✓✓✓✓✓✓…”

Role of Sigma Receptors in Alcohol Addiction

“…Sig-1R has been shown to associate with a variety of proteins such as ankyrin B, heat shock protein 70, phospholipase C, and thus protein kinase C (PKC), protein kinase A, and glucose-related protein/immunoglobulin heavy-chain-binding protein, among others (Morin-Surun et al, 1999; Hayashi and Su, 2001; Matsumoto et al, 2003; Hayashi and Su, 2007; Kim et al, 2008). In addition, Sig-1Rs modulate voltage-gated ion channels, such as the N-type Ca 2+ channel, Nav1.5, Kv1.2, Kv1.3, Kv1.4, and Kv1.5 (Aydar et al, 2002; Balasuriya et al, 2012; Kinoshita et al, 2012; Kourrich et al, 2013; Liu et al, 2017; Zhang et al, 2017). While Sig-1Rs are not G-protein coupled, they physically associate with certain G-protein coupled receptors, such as mu opioid and dopamine D1 and D2 receptors, modulating their activity (Kim et al, 2010; Navarro et al, 2010; Navarro et al, 2013).…”