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

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.

Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K2P background K+ channel TASK-2

“…From a pathophysiological point of view, TASK-2 has been implicated in a predisposition to Balkan endemic nephropathy31 through a dominant negative missense mutation supressing function3233, in the pathogenesis of multiple sclerosis and rheumatoid arthritis in humans34, and in murine inflammatory bowel disease35. TASK-2 is gated by extra- and intracellular pH, changes in cell volume and by Gβγ subunits of G proteins36373839.…”

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

“…3,4,7,8 Indeed, molecules that activate TREK-2 channels have been found to reduce pain. 8 For example, aristolochic acid from plant extracts is a traditional medicine for treating pain and activates TREK-2.…”

“…3,4,7,8 Indeed, molecules that activate TREK-2 channels have been found to reduce pain. 8 For example, aristolochic acid from plant extracts is a traditional medicine for treating pain and activates TREK-2. 8,9 TREK-2 is also activated by arachidonic acid, lysophosphatidic acid, halothane, chloroform, riluzole, chalcones, wagonin, baicalein, 2-aminoethoxydiphenyl borate (2ABP), and ML67-33 10–17 However, while molecules such as aristolochic acid and riluzole have both been shown to reduce peripheral pain signaling, there are currently no selective TREK-2 activators.…”

“…8,9 TREK-2 is also activated by arachidonic acid, lysophosphatidic acid, halothane, chloroform, riluzole, chalcones, wagonin, baicalein, 2-aminoethoxydiphenyl borate (2ABP), and ML67-33 10–17 However, while molecules such as aristolochic acid and riluzole have both been shown to reduce peripheral pain signaling, there are currently no selective TREK-2 activators. 8,18,19 Thus, it is not known whether any of these compounds exhibit their antinociceptive effects via activation of TREK-2 channels. The lack of selective TREK-2 channel activators has impeded characterization of the physiological relevance of TREK-2 in human pain sensation, as well as assessment of the therapeutic potential of activating these channels to reduce postoperative or neuropathic pain.…”

Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia?

“…Certain patients with a predisposition to Balkan endemic nephropathy carry the T108P mutation in TASK-2 (Toncheva et al, 2014); TASK-2 mutant T108P does not generate any significant currents in heterologous expression experiments, and this lack of activity is consistent with a role in Balkan endemic nephropathy (Veale and Mathie, 2016).…”