Startseite Lebenswissenschaften The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition

  • Maurice Dellin EMAIL logo , Ina Rohrbeck , Purva Asrani , Julian A. Schreiber , Nadine Ritter , Frank Glorius , Bernhard Wünsch ORCID logo , Thomas Budde ORCID logo , Louisa Temme , Timo Strünker ORCID logo , Birgit Stallmeyer , Frank Tüttelmann ORCID logo , Sven G. Meuth , Marc Spehr , Johann Matschke ORCID logo , Andrea Steinbicker , Christos Gatsogiannis ORCID logo , Raphael Stoll ORCID logo , Nathalie Strutz-Seebohm und Guiscard Seebohm EMAIL logo
Veröffentlicht/Copyright: 23. Februar 2023
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 404 Heft 4

Abstract

The Phosphatidylinositol 3-phosphate 5-kinase Type III PIKfyve is the main source for selectively generated phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a known regulator of membrane protein trafficking. PI(3,5)P2 facilitates the cardiac KCNQ1/KCNE1 channel plasma membrane abundance and therewith increases the macroscopic current amplitude. Functional-physical interaction of PI(3,5)P2 with membrane proteins and its structural impact is not sufficiently understood. This study aimed to identify molecular interaction sites and stimulatory mechanisms of the KCNQ1/KCNE1 channel via the PIKfyve-PI(3,5)P2 axis. Mutational scanning at the intracellular membrane leaflet and nuclear magnetic resonance (NMR) spectroscopy identified two PI(3,5)P2 binding sites, the known PIP2 site PS1 and the newly identified N-terminal α–helix S0 as relevant for functional PIKfyve effects. Cd2+ coordination to engineered cysteines and molecular modeling suggest that repositioning of S0 stabilizes the channel s open state, an effect strictly dependent on parallel binding of PI(3,5)P2 to both sites.

Keywords: electrophysiology; molecular modeling; phosphatidylinositol; phosphoinositides; phospholipid; potassium channels
Corresponding authors: Maurice Dellin, IfGH–Cellular Electrophysiology, Department of Cardiology and Angiology, University Hospital of Münster, Robert-Koch Str. 45, D-48149, Münster, Germany, E-mail: ; and Guiscard Seebohm, IfGH–Cellular Electrophysiology, Department of Cardiology and Angiology, University Hospital of Münster, Robert-Koch Str. 45, D-48149, Münster, Germany; and GRK 2515, Chemical biology of ion channels (Chembion), Westfälische Wilhelms-Universität Münster, Münster, Germany, E-mail:
Maurice Dellin, Ina Rohrbeck, Nathalie Strutz-Seebohm, and Guiscard Seebohm have contributed equally to this work.

Funding source: Medizinische Fakultät, Westfälische Wilhelms-Universität Münster

Award Identifier / Grant number: Medk

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: CRU326

Award Identifier / Grant number: Chembion

Award Identifier / Grant number: FOR 5146

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: Unassigned

Acknowledgments

We thank G. N. Tseng (Virginia Commonwealth University, Richmond, VA) for providing cysteine-free KCNQ1 mutant channel constructs. We thank Anne Humberg for her excellent technical support. The complete set of NMR spectroscopic data was acquired in 2011 during the master thesis of Ina Rohrbeck (formerly Rothenberg).

  1. Author contributions: MD, IR, NR, JAS, JM, NSS, and GS performed experiments; MD, JAS, and GS performed 3D simulations; NSS, BW, TB, SGM, TS, BS, FT, MS, LT, FG, PA, CG, RS, AS and GS contribute to the experimental design; MD, NSS, and GS wrote the manuscript.

  2. Research funding: This work was supported by the Medizinische Fakultät, Westfälische Wilhelms-Universität Münster, graduate schools Chembion and MedK, Münster, Germany, (grant to MD) and by the Deutsche Forschungsgemeinschaft (FOR 5146 to GS and AS). Further support by the German Research Foundation Clinical Research Unit Male Germ Cells: from Genes to Function (DFG CRU326, grants to FT and TS).

  3. Conflict of interest statement: The authors declare to have no conflict interests.

References

de Araujo, M.E.G., Liebscher, G., Hess, M.W., and Huber, L.A. (2020). Lysosomal size matters. Traffic 21: 60–75, https://doi.org/10.1111/tra.12714.Suche in Google Scholar PubMed PubMed Central

Bargal, R., Avidan, N., Ben-Asher, E., Olender, Z., Zeigler, M., Frumkin, A., Raas-Rothschild, A., Glusman, G., Lancet, D., and Bach, G. (2000). Identification of the gene causing mucolipidosis type IV. Nat. Genet. 26: 118–123, https://doi.org/10.1038/79095.Suche in Google Scholar PubMed

Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M., and Romey, G. (1996). K(v)LQT1 and IsK (minK) proteins associate to form the I-Ks cardiac potassium current. Nature 384: 78–80, https://doi.org/10.1038/384078a0.Suche in Google Scholar PubMed

Berridge, M.J. (1984). Inositol trisphosphate and diacylglycerol as second messengers. Biochem. J. 220: 345–360, https://doi.org/10.1042/bj2200345.Suche in Google Scholar PubMed PubMed Central

Chen, K.E., Healy, M.D., and Collins, B.M. (2019). Towards a molecular understanding of endosomal trafficking by Retromer and Retriever. Traffic 20: 465–478, https://doi.org/10.1111/tra.12649.Suche in Google Scholar PubMed

Cheng, W.W.L., Arcario, M.J., Petroff, J.T. (2021). Druggable lipid binding sites in pentameric ligand-gated ion channels and transient receptor potential channels. Front. Physiol. 12: 798102, https://doi.org/10.3389/fphys.2021.798102.Suche in Google Scholar PubMed PubMed Central

Cullen, P.J. and Steinberg, F. (2018). To degrade or not to degrade: mechanisms and significance of endocytic recycling. Nat. Rev. Mol. Cell Biol. 19: 679–696, https://doi.org/10.1038/s41580-018-0053-7.Suche in Google Scholar PubMed

De Craene, J.O., Bertazzi, D.L., Bar, S., and Friant, S. (2017). Phosphoinositides, major actors in membrane trafficking and lipid signaling pathways. Int. J. Mol. Sci. 18: 634, https://doi.org/10.3390/ijms18030634.Suche in Google Scholar PubMed PubMed Central

Delmas, P. and Brown, D.A. (2005). Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat. Rev. Neurosci. 6: 850–862, https://doi.org/10.1038/nrn1785.Suche in Google Scholar PubMed

Dickson, E.J. and Hille, B. (2019). Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids. Biochem. J. 476: 1–23, https://doi.org/10.1042/bcj20180022.Suche in Google Scholar

Dove, S.K., Dong, K., Kobayashi, T., Williams, F.K., and Michell, R.H. (2009). Phosphatidylinositol 3, 5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function. Biochem. J. 419: 1–13, https://doi.org/10.1042/bj20081950.Suche in Google Scholar PubMed

Eckey, K., Wrobel, E., Strutz-Seebohm, N., Pott, L., Schmitt, N., and Seebohm, G. (2014). Novel K(v)7.1-Phosphatidylinositol 4, 5-bisphosphate interaction sites uncovered by charge neutralization scanning. J. Biol. Chem. 289: 22749–22758, https://doi.org/10.1074/jbc.m114.589796.Suche in Google Scholar PubMed PubMed Central

Gan, N., Han, Y., Zeng, W., Wang, Y., Xue, J., and Jiang, Y. (2022). Structural mechanism of allosteric activation of TRPML1 by PI(3, 5)P2 and rapamycin. Proc. Natl. Acad. Sci. U.S.A. 119: e2120404119, https://doi.org/10.1073/pnas.2120404119.Suche in Google Scholar PubMed PubMed Central

Gehring, E.M., Zurn, A., Klaus, F., Laufer, J., Sopjani, M., Lindner, R., Strutz-Seebohm, N., Tavare, J.M., Boehmer, C., Palmada, M., et al.. (2009). Regulation of the glutamate transporter EAAT2 by PIKfyve. Cell. Physiol. Biochem. 24: 361–368, https://doi.org/10.1159/000257428.Suche in Google Scholar PubMed

Giridharan, S.S.P., Luo, G., Rivero-Rios, P., Steinfeld, N., Tronchere, H., Singla, A., Burstein, E., Billadeau, D.D., Sutton, M.A., and Weisman, L.S. (2022). Lipid kinases VPS34 and PIKfyve coordinate a phosphoinositide cascade to regulate retriever-mediated recycling on endosomes. Elife 11: e69709, https://doi.org/10.7554/elife.69709.Suche in Google Scholar

Grant, B.D. and Donaldson, J.G. (2009). Pathways and mechanisms of endocytic recycling. Nat. Rev. Mol. Cell Biol. 10: 597–608, https://doi.org/10.1038/nrm2755.Suche in Google Scholar PubMed PubMed Central

Hassanin, M., Kerek, E., Chiu, M., Anikovskiy, M., and Prenner, E.J. (2016). Binding affinity of inorganic mercury and cadmium to biomimetic erythrocyte membranes. J. Phys. Chem. B 120: 12872–12882, https://doi.org/10.1021/acs.jpcb.6b10366.Suche in Google Scholar PubMed

Ho, C.Y., Alghamdi, T.A., and Botelho, R.J. (2012). Phosphatidylinositol-3, 5-bisphosphate: no longer the poor PIP2. Traffic 13: 1–8, https://doi.org/10.1111/j.1600-0854.2011.01246.x.Suche in Google Scholar PubMed

Huijbregts, R.P., Topalof, L., and Bankaitis, V.A. (2000). Lipid metabolism and regulation of membrane trafficking. Traffic 1: 195–202, https://doi.org/10.1034/j.1600-0854.2000.010301.x.Suche in Google Scholar PubMed

Hynek, D., Krejcova, L., Sochor, J., Cernei, N., Kynicky, J., Adam, V., Trnkova, L., Hubalek, J., Vrba, R., and Kizek, R. (2012). Study of interactions between cysteine and cadmium(II) ions using automatic pipetting system off-line coupled with electrochemical analyser dedicated United Nation environment program: lead and cadmium initiatives. Int. J. Electrochem. Sci. 7: 1802–1819.Suche in Google Scholar

Ikonomov, O.C., Sbrissa, D., Delvecchio, K., Xie, Y., Jin, J.P., Rappolee, D., and Shisheva, A. (2011). The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice. J. Biol. Chem. 286: 13404–13413, https://doi.org/10.1074/jbc.m111.222364.Suche in Google Scholar PubMed PubMed Central

Iyer, B.R. and Mahalakshmi, R. (2019). Hydrophobic characteristic is energetically preferred for cysteine in a model membrane protein. Biophys. J. 117: 25–35, https://doi.org/10.1016/j.bpj.2019.05.024.Suche in Google Scholar PubMed PubMed Central

Kasimova, M.A., Zaydman, M.A., Cui, J., and Tarek, M. (2015). PIP(2)-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6. Sci. Rep. 5: 7474, https://doi.org/10.1038/srep07474.Suche in Google Scholar PubMed PubMed Central

Kienitz, M.C. and Vladimirova, D. (2015). Synergistic modulation of KCNQ1/KCNE1 K+ channels (IKs) by phosphatidylinositol 4, 5-bisphosphate (PIP2) and [ATP]i. Cell. Signal. 27: 1457–1468, https://doi.org/10.1016/j.cellsig.2015.04.002.Suche in Google Scholar PubMed

Klaus, F., Laufer, J., Czarkowski, K., Strutz-Seebohm, N., Seebohm, G., and Lang, F. (2009). PIKfyve-dependent regulation of the Cl- channel ClC-2. Biochem. Biophys. Res. Commun. 381: 407–411, https://doi.org/10.1016/j.bbrc.2009.02.053.Suche in Google Scholar PubMed

Li, Y., Zaydman, M.A., Wu, D., Shi, J.Y., Guan, M., Virgin-Downey, B., and Cui, J. (2011). KCNE1 enhances phosphatidylinositol 4, 5-bisphosphate (PIP2) sensitivity of I-Ks to modulate channel activity. Proc. Natl. Acad. Sci. U.S.A. 108: 9095–9100, https://doi.org/10.1073/pnas.1100872108.Suche in Google Scholar PubMed PubMed Central

Lopes, C.M., Zhang, H., Rohacs, T., Jin, T., Yang, J., and Logothetis, D.E. (2002). Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron 34: 933–944, https://doi.org/10.1016/s0896-6273(02)00725-0.Suche in Google Scholar PubMed

Matschke, V., Theiss, C., Hollmann, M., Schulze-Bahr, E., Lang, F., Seebohm, G., and Strutz-Seebohm, N. (2015). NDRG2 phosphorylation provides negative feedback for SGK1-dependent regulation of a kainate receptor in astrocytes. Front. Cell. Neurosci. 9: 387, https://doi.org/10.3389/fncel.2015.00387.Suche in Google Scholar PubMed PubMed Central

McCartney, A.J., Zhang, Y., and Weisman, L.S. (2014). Phosphatidylinositol 3, 5-bisphosphate: low abundance, high significance. Bioessays 36: 52–64, https://doi.org/10.1002/bies.201300012.Suche in Google Scholar PubMed PubMed Central

McNally, K.E. and Cullen, P.J. (2018). Endosomal retrieval of cargo: retromer is not alone. Trends Cell Biol. 28: 807–822, https://doi.org/10.1016/j.tcb.2018.06.005.Suche in Google Scholar PubMed

McNally, K.E., Faulkner, R., Steinberg, F., Gallon, M., Ghai, R., Pim, D., Langton, P., Pearson, N., Danson, C.M., Nagele, H., et al.. (2017). Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. Cell Biol. 19: 1214–1225, https://doi.org/10.1038/ncb3610.Suche in Google Scholar PubMed PubMed Central

Morales, K.A., Yang, Y., Long, Z., Li, P., Taylor, A.B., Hart, P.J., and Igumenova, T.I. (2013). Cd2+ as a Ca2+ surrogate in protein-membrane interactions: isostructural but not isofunctional. J. Am. Chem. Soc. 135: 12980–12983, https://doi.org/10.1021/ja406958k.Suche in Google Scholar PubMed PubMed Central

Naslavsky, N. and Caplan, S. (2018). The enigmatic endosome – sorting the ins and outs of endocytic trafficking. J. Cell Sci. 131: jcs216499, https://doi.org/10.1242/jcs.216499.Suche in Google Scholar PubMed PubMed Central

Nebl, T., Oh, S.W., and Luna, E.J. (2000). Membrane cytoskeleton: PIP(2) pulls the strings. Curr. Biol. 10: R351–R354, https://doi.org/10.1016/s0960-9822(00)00465-6.Suche in Google Scholar PubMed

Nerbonne, J.M. and Kass, R.S. (2005). Molecular physiology of cardiac repolarization. Physiol. Rev. 85: 1205–1253, https://doi.org/10.1152/physrev.00002.2005.Suche in Google Scholar PubMed

Pusch, M. (1998). Increase of the single-channel conductance of KvLQT1 potassium channels induced by the association with minK. Pflüger’s Arch 437: 172–174, https://doi.org/10.1007/s004240050765.Suche in Google Scholar PubMed

Rink, J., Ghigo, E., Kalaidzidis, Y., and Zerial, M. (2005). Rab conversion as a mechanism of progression from early to late endosomes. Cell 122: 735–749, https://doi.org/10.1016/j.cell.2005.06.043.Suche in Google Scholar PubMed

Royal, A.A., Tinker, A., and Harmer, S.C. (2017). Phosphatidylinositol-4, 5-bisphosphate is required for KCNQ1/KCNE1 channel function but not anterograde trafficking. PLoS One 12: e0186293, https://doi.org/10.1371/journal.pone.0186293.Suche in Google Scholar PubMed PubMed Central

Rutherford, A.C., Traer, C., Wassmer, T., Pattni, K., Bujny, M.V., Carlton, J.G., Stenmark, H., and Cullen, P.J. (2006). The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport. J. Cell Sci. 119: 3944–3957, https://doi.org/10.1242/jcs.03153.Suche in Google Scholar PubMed PubMed Central

Sanguinetti, M.C., Curran, M.E., Zou, A., Shen, J., Spector, P.S., Atkinson, D.L., and Keating, M.T. (1996). Coassembly of K(v)LQT1 and minK (IsK) proteins to form cardiac I-Ks potassium channel. Nature 384: 80–83, https://doi.org/10.1038/384080a0.Suche in Google Scholar PubMed

Schink, K.O., Tan, K.W., and Stenmark, H. (2016). Phosphoinositides in control of membrane dynamics. Annu. Rev. Cell Dev. Biol. 32: 143–171, https://doi.org/10.1146/annurev-cellbio-111315-125349.Suche in Google Scholar PubMed

Schreiber, J.A., Schepmann, D., Frehland, B., Thum, S., Datunashvili, M., Budde, T., Hollmann, M., Strutz-Seebohm, N., Wunsch, B., and Seebohm, G. (2019). A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors. Commun Biol 2: 420, https://doi.org/10.1038/s42003-019-0645-6.Suche in Google Scholar PubMed PubMed Central

Schreiber, J.A. and Seebohm, G. (2021). Cardiac K+ channels and channelopathies. Handb. Exp. Pharmacol. 267: 113–138.10.1007/164_2021_513Suche in Google Scholar PubMed

Sechi, A.S. and Wehland, J. (2000). The actin cytoskeleton and plasma membrane connection: PtdIns(4, 5)P(2) influences cytoskeletal protein activity at the plasma membrane. J. Cell Sci. 113: 3685–3695, https://doi.org/10.1242/jcs.113.21.3685.Suche in Google Scholar PubMed

Seebohm, G. (2005). Activators of cation channels: potential in treatment of channelopathies. Mol. Pharmacol. 67: 585–588, https://doi.org/10.1124/mol.104.010173.Suche in Google Scholar PubMed

Seebohm, G., Neumann, S., Theiss, C., Novkovic, T., Hill, E.V., Tavare, J.M., Lang, F., Hollmann, M., Manahan-Vaughan, D., and Strutz-Seebohm, N. (2012a). Identification of a novel signaling pathway and its relevance for GluA1 recycling. PLoS One 7: e33889, https://doi.org/10.1371/journal.pone.0033889.Suche in Google Scholar PubMed PubMed Central

Seebohm, G., Strutz-Seebohm, N., Birkin, R., Dell, G., Bucci, C., Spinosa, M.R., Baltaev, R., Mack, A.F., Korniychuk, G., Choudhury, A., et al.. (2007). Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ. Res. 100: 686–692, https://doi.org/10.1161/01.res.0000260250.83824.8f.Suche in Google Scholar

Seebohm, G., Strutz-Seebohm, N., Ureche, O.N., Henrion, U., Baltaev, R., Mack, A.F., Korniychuk, G., Steinke, K., Tapken, D., Pfeufer, A., et al.. (2008). Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of I(Ks) channels. Circ. Res. 103: 1451–U217, https://doi.org/10.1161/circresaha.108.177360.Suche in Google Scholar PubMed

Seebohm, G., Strutz-Seebohm, N., Ursu, O.N., Preisig-Muller, R., Zuzarte, M., Hill, E.V., Kienitz, M.C., Bendahhou, S., Fauler, M., Tapken, D., et al.. (2012b). Altered stress stimulation of inward rectifier potassium channels in Andersen-Tawil syndrome. Faseb. J. 26: 513–522, https://doi.org/10.1096/fj.11-189126.Suche in Google Scholar PubMed

Seebohm, G., Westenskow, P., Lang, F., and Sanguinetti, M.C. (2005). Mutation of colocalized residues of the pore helix and transmembrane segments S5 and S6 disrupt deactivation and modify inactivation of KCNQ1 K+ channels. J. Physiol. 563: 359–368, https://doi.org/10.1113/jphysiol.2004.080887.Suche in Google Scholar PubMed PubMed Central

Selyanko, A.A., Hadley, J.K., Wood, I.C., Abogadie, F.C., Jentsch, T.J., and Brown, D.A. (2000). Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J. Physiol. 522: 349–355, https://doi.org/10.1111/j.1469-7793.2000.t01-2-00349.x.Suche in Google Scholar PubMed PubMed Central

Shisheva, A. (2012). PIKfyve and its Lipid products in health and in sickness. Curr. Top. Microbiol. Immunol. 362: 127–162.10.1007/978-94-007-5025-8_7Suche in Google Scholar PubMed

Simonetti, B. and Cullen, P.J. (2019). Actin-dependent endosomal receptor recycling. Curr. Opin. Cell Biol. 56: 22–33, https://doi.org/10.1016/j.ceb.2018.08.006.Suche in Google Scholar PubMed

Strunk, B.S., Steinfeld, N., Lee, S., Jin, N., Munoz-Rivera, C., Meeks, G., Thomas, A., Akemann, C., Mapp, A.K., MacGurn, J.A., et al.. (2020). Roles for a lipid phosphatase in the activation of its opposing lipid kinase. Mol. Biol. Cell 31: 1835–1845, https://doi.org/10.1091/mbc.e18-09-0556.Suche in Google Scholar

Suh, B.C. and Hille, B. (2002). Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4, 5-bisphosphate synthesis. Neuron 35: 507–520, https://doi.org/10.1016/s0896-6273(02)00790-0.Suche in Google Scholar PubMed

Sun, J. and MacKinnon, R. (2020). Structural basis of human KCNQ1 modulation and gating. Cell 180: 340–347, https://doi.org/10.1016/j.cell.2019.12.003.Suche in Google Scholar PubMed PubMed Central

Takasuga, S., Horie, Y., Sasaki, J., Sun-Wada, G.H., Kawamura, N., Iizuka, R., Mizuno, K., Eguchi, S., Kofuji, S., Kimura, H., et al.. (2013). Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine. Proc. Natl. Acad. Sci. U.S.A. 110: 1726–1731, https://doi.org/10.1073/pnas.1213212110.Suche in Google Scholar PubMed PubMed Central

Tamargo, J., Caballero, R., Gomez, R., Valenzuela, C., and Delpon, E. (2004). Pharmacology of cardiac potassium channels. Cardiovasc. Res. 62: 9–33, https://doi.org/10.1016/j.cardiores.2003.12.026.Suche in Google Scholar PubMed

Taylor, K.C., Kang, P.W., Hou, P., Yang, N.D., Kuenze, G., Smith, J.A., Shi, J., Huang, H., White, K.M., Peng, D., et al.. (2020). Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state. Elife 9: e53901, https://doi.org/10.7554/elife.53901.Suche in Google Scholar

Thomas, A.M., Harmer, S.C., Khambra, T., and Tinker, A. (2011). Characterization of a binding site for anionic phospholipids on KCNQ1. J. Biol. Chem. 286: 2088–2100, https://doi.org/10.1074/jbc.m110.153551.Suche in Google Scholar PubMed PubMed Central

Tristani-Firouzi, M. and Sanguinetti, M.C. (1998). Voltage-dependent inactivation of the human K+ channel KvLQT1 is eliminated by association with minimal K+ channel (minK) subunits. J. Physiol. 510: 37–45, https://doi.org/10.1111/j.1469-7793.1998.037bz.x.Suche in Google Scholar PubMed PubMed Central

Van Kerkhove, E., Pennemans, V., and Swennen, Q. (2010). Cadmium and transport of ions and substances across cell membranes and epithelia. Biometals 23: 823–855, https://doi.org/10.1007/s10534-010-9357-6.Suche in Google Scholar PubMed

Wang, J., Fedoseienko, A., Chen, B., Burstein, E., Jia, D., and Billadeau, D.D. (2018). Endosomal receptor trafficking: retromer and beyond. Traffic 19: 578–590, https://doi.org/10.1111/tra.12574.Suche in Google Scholar PubMed PubMed Central

Wrobel, E., Rothenberg, I., Krisp, C., Hundt, F., Fraenzel, B., Eckey, K., Linders, J.T.M., Gallacher, D.J., Towart, R., Pott, L., et al.. (2016). KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting. Nat. Commun. 7: 12795, https://doi.org/10.1038/ncomms12795.Suche in Google Scholar PubMed PubMed Central

Wrobel, E., Tapken, D., and Seebohm, G. (2012). The KCNE tango – how KCNE1 interacts with Kv7.1. Front. Pharmacol. 3: 142, https://doi.org/10.3389/fphar.2012.00142.Suche in Google Scholar PubMed PubMed Central

Xu, X., Jiang, M., Hsu, K.L., Zhang, M., and Tseng, G.N. (2008). KCNQ1 and KCNE1 in the IKs channel complex make state-dependent contacts in their extracellular domains. J. Gen. Physiol. 131: 589–603, https://doi.org/10.1085/jgp.200809976.Suche in Google Scholar PubMed PubMed Central

Zaydman, M.A., Silva, J.R., Delaloye, K., Li, Y., Liang, H.W., Larsson, H.P., Shi, J.Y., and Cui, J.M. (2013). Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening. Proc. Natl. Acad. Sci. U.S.A. 110: 13180–13185, https://doi.org/10.1073/pnas.1305167110.Suche in Google Scholar PubMed PubMed Central

Zegzhda, G.D., Kabanova, V.N., and Tulyupa, F.M. (1975). Cadmium complexes with cysteine. Zh. Neorg. Khim. 20: 2325–2329.Suche in Google Scholar

Zhang, H., Craciun, L.C., Mirshahi, T., Rohacs, T., Lopes, C.M., Jin, T., and Logothetis, D.E. (2003). PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37: 963–975, https://doi.org/10.1016/s0896-6273(03)00125-9.Suche in Google Scholar PubMed

Zitka, O., Sochor, J., Cernei, N., Adam, V., Zehnalek, J., Horna, A., Hubalek, J., Trnkova, L., Havel, L., and Kizek, R. (2010). A study of interaction of cadmium(II) ions with cysteine. Listy Cukrov. a Reparske 126: 422.Suche in Google Scholar

Zolov, S.N., Bridges, D., Zhang, Y., Lee, W.W., Riehle, E., Verma, R., Lenk, G.M., Converso-Baran, K., Weide, T., Albin, R.L., et al.. (2012). In vivo, Pikfyve generates PI(3, 5)P2, which serves as both a signaling lipid and the major precursor for PI5P. Proc. Natl. Acad. Sci. U.S.A. 109: 17472–17477, https://doi.org/10.1073/pnas.1203106109.Suche in Google Scholar PubMed PubMed Central

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/hsz-2022-0247).

Received: 2022-08-05
Accepted: 2022-12-13
Published Online: 2023-02-23
Published in Print: 2023-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
https://doi.org/10.1515/hsz-2022-0247
Schlagwörter für diesen Artikel
electrophysiology; molecular modeling; phosphatidylinositol; phosphoinositides; phospholipid; potassium channels

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2026 De Gruyter Brill
Heruntergeladen am 7.1.2026 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2022-0247/pdf
Button zum nach oben scrollen