title: Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels.
abstract: 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.
  
  
  
  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.
  
  
  
  TREK-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.
  
  
  
  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.
authors.affiliation: Medway School of Pharmacy, University of Kent, Kent, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Veale
authors.affiliation: Medway School of Pharmacy, University of Kent, Kent, UK.
authors.forename: Alistair
authors.initials: A
authors.lastname: Mathie
mesh_terms: D034341:Aristolochic Acids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001449:Balkan Nephropathy / Q000188:drug therapy*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D010936:Plant Extracts / Q000737:chemistry*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D034341:Aristolochic Acids; D010936:Plant Extracts; D024683:Potassium Channels, Tandem Pore Domain; C000228:aristolochic acid I