ArticlePhysiological reports2019
The LRRC8 volume-regulated anion channel inhibitor, DCPIB, inhibits mitochondrial respiration independently of the channel.
Article in Physiological reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- State-dependent inhibition of LRRC8 volume-regulated anion channels by DCPIB.The Journal of general physiology · 2026Article
- A nonhydrolyzable candesartan cilexetil analog reveals synergistic activation as a tractable mechanism for TMEM175 modulation.American journal of physiology. Cell physiology · 2026Article
- Binding to Albumin and Off-Target Toxicity Confound the Use of LRRC8/VRAC Channel Blockers in Cell Physiology Assays.bioRxiv : the preprint server for biology · 2026Article
- LRRC8A-containing anion channels promote glioblastoma proliferation via a WNK1/mTORC2-dependent mechanism.The Journal of physiology · 2026Article
- Mechanism of action of two potent LRRC8/VRAC channel inhibitors.Research square · 2026Article
- A conserved mechanism of LRRC8 channel inhibition by two structurally distinct drugs.Communications biology · 2025Article
- Excitotoxic neuronal death requires superoxide entry into neurons through volume-regulated anion channels.Science advances · 2025Article
- Recent advances in the structure, function and regulation of the volume-regulated anion channels and their role in immunity.The Journal of physiology · 2025Review
- Separate mechanisms regulating accumbal taurine levels during baseline conditions and following ethanol exposure in the rat.Scientific reports · 2024Article
- Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels.Hypertension (Dallas, Tex. : 1979) · 2024Review
- Mitochondrial dysfunction is a key link involved in the pathogenesis of sick sinus syndrome: a review.Frontiers in cardiovascular medicine · 2024Review
- Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function.Nature communications · 2023Article
- Article
- Structural and functional analysis of human pannexin 2 channel.Nature communications · 2023Article
- A SWELL time to develop the molecular pharmacology of the volume-regulated anion channel (VRAC).Channels (Austin, Tex.) · 2022Review
- LRRC8A is dispensable for a variety of microglial functions and response to acute stroke.Glia · 2022Article
- Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.Nature communications · 2022Article
- Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8.Frontiers in pharmacology · 2022Review
- Chloride transport modulators as drug candidates.American journal of physiology. Cell physiology · 2021Review
- Zinc pyrithione activates the volume-regulated anion channel through an antioxidant-sensitive mechanism.American journal of physiology. Cell physiology · 2021Article
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Authors and funding
7 authors.
Funding
Abstract
There has been a resurgence of interest in the volume-regulated anion channel (VRAC) since the recent cloning of the LRRC8A-E gene family that encodes VRAC. The channel is a heteromer comprised of LRRC8A and at least one other family member; disruption of LRRC8A expression abolishes VRAC activity. The best-in-class VRAC inhibitor, DCPIB, suffers from off-target activity toward several different channels and transporters. Considering that some anion channel inhibitors also suppress mitochondrial respiration, we systematically explored whether DCPIB inhibits respiration in wild type (WT) and LRRC8A-knockout HAP-1 and HEK-293 cells. Knockout of LRRC8A had no apparent effects on cell morphology, proliferation rate, mitochondrial content, or expression of several mitochondrial genes in HAP-1 cells. Addition of 10 µM DCPIB, a concentration typically used to inhibit VRAC, suppressed basal and ATP-linked respiration in part through uncoupling the inner mitochondrial membrane (IMM) proton gradient and membrane potential. Additionally, DCPIB inhibits the activity of complex I, II, and III of the electron transport chain (ETC). Surprisingly, the effects of DCPIB on mitochondrial function are also observed in HAP-1 and HEK-293 cells which lack LRRC8A expression. Finally, we demonstrate that DCPIB activates ATP-inhibitable potassium channels comprised of heterologously expressed Kir6.2 and SUR1 subunits. These data indicate that DCPIB suppresses mitochondrial respiration and ATP production by dissipating the mitochondrial membrane potential and inhibiting complexes I-III of the ETC. They further justify the need for the development of sharper pharmacological tools for evaluating the integrative physiology and therapeutic potential of VRAC in human diseases.
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