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.
Cohen
Asi
A
Department of Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Sagron
Revital
R
Somech
Erez
E
Segal-Hayoun
Yifat
Y
Zilberberg
Noam
N
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008246:Lysophospholipids / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D010146:Pain / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D014982:Xenopus laevis
D008246:Lysophospholipids; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; C032881:lysophosphatidic acid