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Open AccessFeature PaperArticle

Direct Activation of TRPC3 Channels by the Antimalarial Agent Artemisinin

Leipzig University, Medical Faculty, Rudolf Boehm Institute of Pharmacology and Toxicology, Härtelstraße 16-18, 04107 Leipzig, Germany
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Cells 2020, 9(1), 202; https://doi.org/10.3390/cells9010202 (registering DOI)
Received: 29 November 2019 / Revised: 27 December 2019 / Accepted: 9 January 2020 / Published: 14 January 2020
(This article belongs to the Special Issue TRPC Channels)
(1) Background: Members of the TRPC3/TRPC6/TRPC7 subfamily of canonical transient receptor potential (TRP) channels share an amino acid similarity of more than 80% and can form heteromeric channel complexes. They are directly gated by diacylglycerols in a protein kinase C-independent manner. To assess TRPC3 channel functions without concomitant protein kinase C activation, direct activators are highly desirable. (2) Methods: By screening 2000 bioactive compounds in a Ca2+ influx assay, we identified artemisinin as a TRPC3 activator. Validation and characterization of the hit was performed by applying fluorometric Ca2+ influx assays and electrophysiological patch-clamp experiments in heterologously or endogenously TRPC3-expressing cells. (3) Results: Artemisinin elicited Ca2+ entry through TRPC3 or heteromeric TRPC3:TRPC6 channels, but did not or only weakly activated TRPC6 and TRPC7. Electrophysiological recordings confirmed the reversible and repeatable TRPC3 activation by artemisinin that was inhibited by established TRPC3 channel blockers. Rectification properties and reversal potentials were similar to those observed after stimulation with a diacylglycerol mimic, indicating that artemisinin induces a similar active state as the physiological activator. In rat pheochromocytoma PC12 cells that endogenously express TRPC3, artemisinin induced a Ca2+ influx and TRPC3-like currents. (4) Conclusions: Our findings identify artemisinin as a new biologically active entity to activate recombinant or native TRPC3-bearing channel complexes in a membrane-confined fashion. View Full-Text
Keywords: transient receptor potential canonical; Artemisia annua; secondary plant metabolites; high-throughput compound screening; membrane-delimited activator; non-selective cation channel; intracellular calcium homeostasis transient receptor potential canonical; Artemisia annua; secondary plant metabolites; high-throughput compound screening; membrane-delimited activator; non-selective cation channel; intracellular calcium homeostasis
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Urban, N.; Schaefer, M. Direct Activation of TRPC3 Channels by the Antimalarial Agent Artemisinin. Cells 2020, 9, 202.

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