4bw5 Citations

K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac.


TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.

Reviews - 4bw5 mentioned but not cited (1)

  1. Molecular aspects of structure, gating, and physiology of pH-sensitive background K2P and Kir K+-transport channels. Sepúlveda FV, Pablo Cid L, Teulon J, Niemeyer MI. Physiol. Rev. 95 179-217 (2015)

Articles - 4bw5 mentioned but not cited (1)

  1. Differential sensitivity of TREK-1, TREK-2 and TRAAK background potassium channels to the polycationic dye ruthenium red. Braun G, Lengyel M, Enyedi P, Czirják G. Br. J. Pharmacol. 172 1728-1738 (2015)

Reviews citing this publication (8)

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  7. How ion channels sense mechanical force: insights from mechanosensitive K2P channels TRAAK, TREK1, and TREK2. Brohawn SG. Ann. N. Y. Acad. Sci. 1352 20-32 (2015)
  8. Mechanically Activated Ion Channels. Ranade SS, Syeda R, Patapoutian A. Neuron 87 1162-1179 (2015)

Articles citing this publication (37)

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  11. Serotonergic agents act on 5-HT3 receptors in the brain to block seizure-induced respiratory arrest in the DBA/1 mouse model of SUDEP. Faingold CL, Randall M, Zeng C, Peng S, Long X, Feng HJ. Epilepsy Behav 64 166-170 (2016)
  12. Modulation of Potassium Channels Inhibits Bunyavirus Infection. Hover S, King B, Hall B, Loundras EA, Taqi H, Daly J, Dallas M, Peers C, Schnettler E, McKimmie C, Kohl A, Barr JN, Mankouri J. J. Biol. Chem. 291 3411-3422 (2016)
  13. Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore. Chokshi RH, Larsen AT, Bhayana B, Cotten JF. Mol. Pharmacol. 88 926-934 (2015)
  14. K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site. Lolicato M, Arrigoni C, Mori T, Sekioka Y, Bryant C, Clark KA, Minor DL. Nature 547 364-368 (2017)
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  21. Stretch-activated two-pore-domain (K2P) potassium channels in the heart: Focus on atrial fibrillation and heart failure. Schmidt C, Wiedmann F, Kallenberger SM, Ratte A, Schulte JS, Scholz B, Müller FU, Voigt N, Zafeiriou MP, Ehrlich JR, Tochtermann U, Veres G, Ruhparwar A, Karck M, Katus HA, Thomas D. Prog. Biophys. Mol. Biol. (2017)
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  23. Genome-Wide Transcriptome Analysis of CD36 Overexpression in HepG2.2.15 Cells to Explore Its Regulatory Role in Metabolism and the Hepatitis B Virus Life Cycle. Huang J, Zhao L, Yang P, Chen Z, Tang N, Z Ruan X, Chen Y. PLoS ONE 11 e0164787 (2016)
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  34. A Soluble Fluorescent Binding Assay Reveals PIP2 Antagonism of TREK-1 Channels. Cabanos C, Wang M, Han X, Hansen SB. Cell Rep 20 1287-1294 (2017)
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