Pain-associated signals, acidosis and lysophosphatidic acid, modulate the neuronal K(2P)2.1 channel.

Pain is a physiological state promoting protective responses to harmful episodes. However, pain can become pathophysiological and become a chronic disruptive condition, damaging quality of life. The mammalian K(2P)2.1 (KCNK2, TREK-1) channel, expressed in sensory neurons of the dorsal root ganglia, was previously identified as a polymodal molecular sensor involved in pain perception. Here, we report that two pain-associated signals, external acidosis and lysophosphatidic acid (LPA), known to rise during injury, inflammation and cancer, profoundly down-modulate human K(2P)2.1 activity. The pH regulatory effect was mediated by activation of proton-sensitive G-protein coupled receptors and phospholipase C. Physiological concentrations of LPA overcame the effects of known K(2P)2.1 activators, such as arachidonic acid, lysophosphatidylcholine and temperature, by activating cell-surface receptors stimulating the G(q) pathway. Furthermore, we identified three K(2P)2.1 carboxy-terminal residues that mediate both pH and LPA regulatory effects. Our results highlight the important role of K(2P)2.1 channels as receptors for mediators known to cause nociception.

Isolation of the first toxin from the scorpion Buthus occitanus israelis showing preference for Shaker potassium channels.

We have purified BoiTx1, the first toxin from the venom of the Israeli scorpion, Buthus occitanus israelis, and studied its activity and genomic organization. BoiTx1 is a 37 amino acid-long peptide contained six conserved cysteines, and is classified as an alpha-KTx3.10 toxin. The pharmacological effects of BoiTx1 were studied on various cloned K(+) channels expressed in Xenopus laevis oocytes. BoiTx1 inhibited currents through Drosophila Shaker channels with an IC(50) value of 3.5+/-0.5nM, yet had much lesser effect on its mammalian orthologs. Thus, BoiTx1 is the first member of the alpha-KTx3 family that preferentially affects insect potassium channels.