4bw5 Citations

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

Abstract

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)

  1. Spectator no more, the role of the membrane in regulating ion channel function. Pliotas C, Naismith JH. Curr. Opin. Struct. Biol. 45 59-66 (2017)
  2. Stretch-activated potassium currents in the heart: Focus on TREK-1 and arrhythmias. Decher N, Kiper AK, Rinné S. Prog. Biophys. Mol. Biol. (2017)
  3. Gating, Regulation, and Structure in K2P K+ Channels: In Varietate Concordia? Niemeyer MI, Cid LP, González W, Sepúlveda FV. Mol. Pharmacol. 90 309-317 (2016)
  4. Two-pore Domain Potassium Channels in Astrocytes. Ryoo K, Park JY. Exp Neurobiol 25 222-232 (2016)
  5. Much more than a leak: structure and function of K₂p-channels. Renigunta V, Schlichthörl G, Daut J. Pflugers Arch. 467 867-894 (2015)
  6. Structure of potassium channels. Kuang Q, Purhonen P, Hebert H. Cell. Mol. Life Sci. 72 3677-3693 (2015)
  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)

  1. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Ahuja S, Mukund S, Deng L, Khakh K, Chang E, Ho H, Shriver S, Young C, Lin S, Johnson JP, Wu P, Li J, Coons M, Tam C, Brillantes B, Sampang H, Mortara K, Bowman KK, Clark KR, Estevez A, Xie Z, Verschoof H, Grimwood M, Dehnhardt C, Andrez JC, Focken T, Sutherlin DP, Safina BS, Starovasnik MA, Ortwine DF, Franke Y, Cohen CJ, Hackos DH, Koth CM, Payandeh J. Science 350 aac5464 (2015)
  2. Piezo1 Channels Are Inherently Mechanosensitive. Syeda R, Florendo MN, Cox CD, Kefauver JM, Santos JS, Martinac B, Patapoutian A. Cell Rep 17 1739-1746 (2016)
  3. A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels. Schewe M, Nematian-Ardestani E, Sun H, Musinszki M, Cordeiro S, Bucci G, de Groot BL, Tucker SJ, Rapedius M, Baukrowitz T. Cell 164 937-949 (2016)
  4. The role of MscL amphipathic N terminus indicates a blueprint for bilayer-mediated gating of mechanosensitive channels. Bavi N, Cortes DM, Cox CD, Rohde PR, Liu W, Deitmer JW, Bavi O, Strop P, Hill AP, Rees D, Corry B, Perozo E, Martinac B. Nat Commun 7 11984 (2016)
  5. Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels. Levitz J, Royal P, Comoglio Y, Wdziekonski B, Schaub S, Clemens DM, Isacoff EY, Sandoz G. Proc. Natl. Acad. Sci. U.S.A. 113 4194-4199 (2016)
  6. Insights into the stimulatory mechanism of 2-aminoethoxydiphenyl borate on TREK-2 potassium channel. Zhuo RG, Liu XY, Zhang SZ, Wei XL, Zheng JQ, Xu JP, Ma XY. Neuroscience 300 85-93 (2015)
  7. Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties. Blin S, Ben Soussia I, Kim EJ, Brau F, Kang D, Lesage F, Bichet D. Proc. Natl. Acad. Sci. U.S.A. 113 4200-4205 (2016)
  8. Early-life serotonin dysregulation affects the migration and positioning of cortical interneuron subtypes. Frazer S, Otomo K, Dayer A. Transl Psychiatry 5 e644 (2015)
  9. Calcium ions open a selectivity filter gate during activation of the MthK potassium channel. Posson DJ, Rusinova R, Andersen OS, Nimigean CM. Nat Commun 6 8342 (2015)
  10. Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. Aryal P, Jarerattanachat V, Clausen MV, Schewe M, McClenaghan C, Argent L, Conrad LJ, Dong YY, Pike ACW, Carpenter EP, Baukrowitz T, Sansom MSP, Tucker SJ. Structure 25 708-718.e2 (2017)
  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)
  15. Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states. McClenaghan C, Schewe M, Aryal P, Carpenter EP, Baukrowitz T, Tucker SJ. J. Gen. Physiol. 147 497-505 (2016)
  16. Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy. Reed AP, Bucci G, Abd-Wahab F, Tucker SJ. PLoS ONE 11 e0156456 (2016)
  17. Scanning MscL Channels with Targeted Post-Translational Modifications for Functional Alterations. Iscla I, Wray R, Eaton C, Blount P. PLoS ONE 10 e0137994 (2015)
  18. Functional mutagenesis screens reveal the 'cap structure' formation in disulfide-bridge free TASK channels. Goldstein M, Rinné S, Kiper AK, Ramírez D, Netter MF, Bustos D, Ortiz-Bonnin B, González W, Decher N. Sci Rep 6 19492 (2016)
  19. Allosteric coupling between proximal C-terminus and selectivity filter is facilitated by the movement of transmembrane segment 4 in TREK-2 channel. Zhuo RG, Peng P, Liu XY, Yan HT, Xu JP, Zheng JQ, Wei XL, Ma XY. Sci Rep 6 21248 (2016)
  20. The effects of stretch activation on ionic selectivity of the TREK-2 K2P K+ channel. Nematian-Ardestani E, Jarerattanachat V, Aryal P, Sansom MSP, Tucker SJ. Channels (Austin) 11 482-486 (2017)
  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)
  22. Functional Annotation of Ion Channel Structures by Molecular Simulation. Trick JL, Chelvaniththilan S, Klesse G, Aryal P, Wallace EJ, Tucker SJ, Sansom MS. Structure 24 2207-2216 (2016)
  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)
  24. Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K2P18.1. Monteillier A, Loucif A, Omoto K, Stevens EB, Lainez S, Saintot PP, Cao L, Pryde DC. Bioorg. Med. Chem. Lett. 26 4919-4924 (2016)
  25. Exploring the Dynamics of the TWIK-1 Channel. Oakes V, Furini S, Pryde D, Domene C. Biophys. J. 111 775-784 (2016)
  26. Paramagnetic effects on the NMR spectra of isotropic bicelles with headgroup modified chelator lipids and metal ions. Tang M, Mao K, Li S, Zhuang J, Diallo K. Phys Chem Chem Phys 18 15524-15527 (2016)
  27. Understanding the Cap Structure in K2P Channels. Zúñiga L, Zúñiga R. Front Physiol 7 228 (2016)
  28. Mesitylene-Cored Glucoside Amphiphiles (MGAs) for Membrane Protein Studies: Importance of Alkyl Chain Density in Detergent Efficacy. Cho KH, Ribeiro O, Du Y, Tikhonova E, Mortensen JS, Markham K, Hariharan P, Loland CJ, Guan L, Kobilka BK, Byrne B, Chae PS. Chemistry 22 18833-18839 (2016)
  29. GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels. Gnanasambandam R, Ghatak C, Yasmann A, Nishizawa K, Sachs F, Ladokhin AS, Sukharev SI, Suchyna TM. Biophys. J. 112 31-45 (2017)
  30. Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter. Harrigan MP, McKiernan KA, Shanmugasundaram V, Denny RA, Pande VS. Sci Rep 7 632 (2017)
  31. Tandem malonate-based glucosides (TMGs) for membrane protein structural studies. Hussain H, Mortensen JS, Du Y, Santillan C, Ribeiro O, Go J, Hariharan P, Loland CJ, Guan L, Kobilka BK, Byrne B, Chae PS. Sci Rep 7 3963 (2017)
  32. The glycine hinge of transmembrane segment 2 modulates the subcellular localization and gating properties in TREK channels. Zhuo RG, Peng P, Zheng JQ, Zhang YL, Wen L, Wei XL, Ma XY. Biochem. Biophys. Res. Commun. 490 1125-1131 (2017)
  33. Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins. Stock L, Hosoume J, Treptow W. Sci Rep 7 5734 (2017)
  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)
  35. An allosteric ligand-binding site in the extracellular cap of K2P channels. Luo Q, Chen L, Cheng X, Ma Y, Li X, Zhang B, Li L, Zhang S, Guo F, Li Y, Yang H. Nat Commun 8 378 (2017)
  36. Asymmetric mechanosensitivity in a eukaryotic ion channel. Clausen MV, Jarerattanachat V, Carpenter EP, Sansom MSP, Tucker SJ. Proc. Natl. Acad. Sci. U.S.A. 114 E8343-E8351 (2017)
  37. Mechanism of activation at the selectivity filter of the KcsA K+ channel. Heer FT, Posson DJ, Wojtas-Niziurski W, Nimigean CM, Bernèche S, Bernèche S. Elife 6 (2017)