Abstract
Background and PurposeAristolochic 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 (K2P5.1) channels (T108P) is seen in some patients susceptible to BEN, so we investigated how both this mutation and AristA affected TASK‐2 channels.Experimental ApproachCurrents 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 ResultsTREK‐1‐ and TREK‐2‐mediated currents were enhanced by AristA (100 μM), 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 μM) produced a modest enhancement of TASK‐2 current.Conclusions and ImplicationsEnhancement 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.
Highlights
Aristolochic acid (AristA) is found in plants of the Aristolochiaceae family, which have been used widely in traditional medicine for thousands of years
We investigated the effect of this double mutation on the action of AristA on TRESK channels
We considered whether activators of TASK-2 channels might induce current through T108P mutated channels, as has been seen previously for other non-functional or reduced-function, mutated K2P channels (Ma et al, 2013; V eale et al, 2014a,b)
Summary
Aristolochic acid (AristA) is found in plants of the Aristolochiaceae family, which have been used widely in traditional medicine for thousands of years These plants are mentioned in early first-century Roman texts as components of frequently ingested medicines to treat a variety of conditions including asthma, hiccups, spasms, pains and expulsion of afterbirth, and they were described as components of certain Chinese herbal medicines in the fifth century AD (Scarborough, 2011). These herbal remedies were used for a variety of conditions, a recurring theme was their use in many cultures for the treatment of pain. Currents through wild-type and mutated human K2P channels expressed in tsA201 cells were measured using whole-cell patchclamp recordings in the presence and absence of AristA
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