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Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue
Michel Lazdunski, and
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6097, Université de Nice Sophia-Antipolis, 660 route des lucioles, Sophia-Antipolis, 06560 Valbonne, France
Edited by Lily Y. Jan, University of California, San Francisco, CA, and approved July 10, 2009
Received for publication June 9, 2009.
Mechanosensitive K+ channels TREK1 and TREK2 form a subclassof two P-domain K+ channels. They are potently activated bypolyunsaturated fatty acids and are involved in neuroprotection,anesthesia, and pain perception. Here, we show that acidificationof the extracellular medium strongly inhibits TREK1 with anapparent pK near to 7.4 corresponding to the physiological pH.The all-or-none effect of pH variation is steep and is observedwithin one pH unit. TREK2 is not inhibited but activated byacidification within the same range of pH, despite its closehomology with TREK1. A single conserved residue, H126 in TREK1and H151 in TREK2, is involved in proton sensing. This histidineis located in the M1P1 extracellular loop preceding the firstP domain. The differential effect of acidification, that is,activation for TREK2 and inhibition for TREK1, involves otherresidues located in the P2M4 loop, linking the second P domainand the fourth membrane-spanning segment. Structural modelingof TREK1 and TREK2 and site-directed mutagenesis strongly suggestthat attraction or repulsion between the protonated side chainof histidine and closely located negatively or positively chargedresidues in P2M4 control outer gating of these channels. Thedifferential sensitivity of TREK1 and TREK2 to external pH variationsdiscriminates between these two K+ channels that otherwise sharethe same regulations by physical and chemical stimuli, and byhormones and neurotransmitters.
Key Words: ion channel mutagenesis structural modeling
Author contributions: G.S., D.D., and F.L. designed research;G.S., D.D., and F.C. performed research; F.C. contributed newreagents/analytic tools; G.S., D.D., M.L., and F.L. analyzeddata; and G.S., D.D., M.L., and F.L. wrote the paper.