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Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

Veale, Emma L., Mathie, Alistair (2016) Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels. British Journal of Pharmacology, 173 (10). pp. 1639-1652. ISSN 0007-1188. E-ISSN 1476-5381. (doi:10.1111/bph.13465) (KAR id:56160)


Background and Purpose: Aristolochic acid (AristA) is found in plants used in traditional medicines to treat pain. We investigated the action of AristA on TREK and TRESK, potassium (K2P) channels, which are potential therapeutic targets in pain. Balkan endemic nephropathy (BEN) is a renal disease associated with AristA consumption. A mutation of TASK-2 (K2P 5.1) channels (T108P) is seen in some patients susceptible to BEN, so we investigated how both this mutation and AristA affected TASK-2 channels.

Experimental Approach: Currents through wild-type and mutated human K2P channels expressed in tsA201 cells were measured using whole-cell patch-clamp recordings in the presence and absence of AristA.

Key Results: TREK-1- and TREK-2-mediated currents were enhanced by AristA (100 ?M), whereas TRESK was inhibited. Inhibition of TRESK did not depend on the phosphorylation of key intracellular serines but was completely blocked by mutation of bulky residues in the inner pore (F145A_F352A). The TASK-2_T108P mutation markedly reduced both current density and ion selectivity. A related mutation (T108C) had similar but less marked effects. External alkalization and application of flufenamic acid enhanced TASK-2 and TASK-2_T108C current but did not affect TASK-2_T108P current. AristA (300 ?M) produced a modest enhancement of TASK-2 current.

Conclusions and Implications: Enhancement of TREK-1 and TREK-2 and inhibition of TRESK by AristA may contribute to therapeutically useful effects of this compound in pain. Whilst AristA is unlikely to interact directly with TASK-2 channels in BEN, loss of functional TASK-2 channels may indirectly increase susceptibility to AristA toxicity.

Item Type: Article
DOI/Identification number: 10.1111/bph.13465
Uncontrolled keywords: Medway School of Pharmacy
Subjects: Q Science > QP Physiology (Living systems) > QP506 Molecular biology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Alistair Mathie
Date Deposited: 28 Jun 2016 14:07 UTC
Last Modified: 16 Feb 2021 13:35 UTC
Resource URI: (The current URI for this page, for reference purposes)

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