Regulation of Two-pore-domain (K2P) Potassium Leak Channels by the Tyrosine Kinase Inhibitor Genistein

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2008 Jun 3

PMID 18516069

Citations 28

Authors

J Gierten

E Ficker

R Bloehs

K Schlomer

S Kathofer

E Scholz

E Zitron

C Kiesecker

A Bauer

R Becker

H A Katus

C A Karle

D Thomas

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Two-pore-domain potassium (K2P) channels mediate potassium background (or 'leak') currents, controlling excitability by stabilizing membrane potential below firing threshold and expediting repolarization. Inhibition of K2P currents permits membrane potential depolarization and excitation. As expected for key regulators of excitability, leak channels are under tight control from a plethora of stimuli. Recently, signalling via protein tyrosine kinases (TKs) has been implicated in ion channel modulation. The objective of this study was to investigate TK regulation of K2P channels.

Experimental Approach: The two-electrode voltage clamp technique was used to record K2P currents in Xenopus oocytes. In addition, K2P channels were studied in Chinese hamster ovary (CHO) cells using the whole-cell patch clamp technique.

Key Results: Here, we report inhibition of human K2P3.1 (TASK-1) currents by the TK antagonist, genistein, in Xenopus oocytes (IC50=10.7 microM) and in CHO cells (IC50=12.3 microM). The underlying molecular mechanism was studied in detail. hK2P3.1 was not affected by genistin, an inactive analogue of genistein. Perorthovanadate, an inhibitor of tyrosine phosphatase activity, reduced the inhibitory effect of genistein. Current reduction was voltage independent and did not require channel protonation at position H98 or phosphorylation at the single TK phosphorylation site, Y323. Among functional hK2P family members, genistein also reduced K2P6.1 (TWIK-2), K2P9.1 (TASK-3) and K2P13.1 (THIK-1) currents, respectively.

Conclusions And Implications: Modulation of K2P channels by the TK inhibitor, genistein, represents a novel molecular mechanism to alter background K+ currents.

Citing Articles

Electrophysiological Effects of the Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitor Dapagliflozin on Human Cardiac Potassium Channels.

Muller M, Petersenn F, Hackbarth J, Pfeiffer J, Gampp H, Frey N Int J Mol Sci. 2024; 25(11).

PMID: 38891889 PMC: 11172209. DOI: 10.3390/ijms25115701.

KCNK9 mediates the inhibitory effects of genistein on hepatic metastasis from colon cancer.

Cheng Y, Tang Y, Tan Y, Li J, Zhang X Clinics (Sao Paulo). 2023; 78:100141.

PMID: 36905879 PMC: 10019991. DOI: 10.1016/j.clinsp.2022.100141.

Flavonoids as Modulators of Potassium Channels.

Richter-Laskowska M, Trybek P, Delfino D, Wawrzkiewicz-Jalowiecka A Int J Mol Sci. 2023; 24(2).

PMID: 36674825 PMC: 9861088. DOI: 10.3390/ijms24021311.

The Advantages, Challenges, and Future of Human-Induced Pluripotent Stem Cell Lines in Type 2 Long QT Syndrome.

Cai D, Zheng Z, Jin X, Fu Y, Cen L, Ye J J Cardiovasc Transl Res. 2022; 16(1):209-220.

PMID: 35976484 DOI: 10.1007/s12265-022-10298-x.

Two-Pore-Domain Potassium (K-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes.

Wiedmann F, Frey N, Schmidt C Cells. 2021; 10(11).

PMID: 34831137 PMC: 8616229. DOI: 10.3390/cells10112914.

References

Putzke C, Wemhoner K, Sachse F, Rinne S, Schlichthorl G, Li X . The acid-sensitive potassium channel TASK-1 in rat cardiac muscle. Cardiovasc Res. 2007; 75(1):59-68. DOI: 10.1016/j.cardiores.2007.02.025. View

Lalevee N, Monier B, Senatore S, Perrin L, Semeriva M . Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel. Curr Biol. 2006; 16(15):1502-8. DOI: 10.1016/j.cub.2006.05.064. View

Patel A, Honore E, Maingret F, Lesage F, Fink M, Duprat F . A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J. 1998; 17(15):4283-90. PMC: 1170762. DOI: 10.1093/emboj/17.15.4283. View

Wischmeyer E, Doring F, Karschin A . Acute suppression of inwardly rectifying Kir2.1 channels by direct tyrosine kinase phosphorylation. J Biol Chem. 1998; 273(51):34063-8. DOI: 10.1074/jbc.273.51.34063. View

Cohen A, Zilberberg N . Fluctuations in Xenopus oocytes protein phosphorylation levels during two-electrode voltage clamp measurements. J Neurosci Methods. 2005; 153(1):62-70. DOI: 10.1016/j.jneumeth.2005.10.005. View

Fryer R, Schultz J, Hsu A, Gross G . Pretreatment with tyrosine kinase inhibitors partially attenuates ischemic preconditioning in rat hearts. Am J Physiol. 1998; 275(6):H2009-15. DOI: 10.1152/ajpheart.1998.275.6.H2009. View

Thomas D, Zhang W, Karle C, Kathofer S, Schols W, Kubler W . Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A. J Biol Chem. 1999; 274(39):27457-62. DOI: 10.1074/jbc.274.39.27457. View

Mathie A . Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J Physiol. 2006; 578(Pt 2):377-85. PMC: 2075148. DOI: 10.1113/jphysiol.2006.121582. View

Veale E, Kennard L, Sutton G, MacKenzie G, Sandu C, Mathie A . G(alpha)q-mediated regulation of TASK3 two-pore domain potassium channels: the role of protein kinase C. Mol Pharmacol. 2007; 71(6):1666-75. DOI: 10.1124/mol.106.033241. View

10.

Bayliss D, Sirois J, Talley E . The TASK family: two-pore domain background K+ channels. Mol Interv. 2004; 3(4):205-19. DOI: 10.1124/mi.3.4.205. View

11.

Kang D, Choe C, Kim D . Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. J Physiol. 2005; 564(Pt 1):103-16. PMC: 1456046. DOI: 10.1113/jphysiol.2004.081059. View

12.

Ogata R, Kitamura K, Ito Y, Nakano H . Inhibitory effects of genistein on ATP-sensitive K+ channels in rabbit portal vein smooth muscle. Br J Pharmacol. 1998; 122(7):1395-404. PMC: 1565089. DOI: 10.1038/sj.bjp.0701532. View

13.

Patel A, Honore E . Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci. 2001; 24(6):339-46. DOI: 10.1016/s0166-2236(00)01810-5. View

14.

ODell T, Kandel E, Grant S . Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors. Nature. 1991; 353(6344):558-60. DOI: 10.1038/353558a0. View

15.

Benter I, Juggi J, Khan I, Yousif M, Canatan H, Akhtar S . Signal transduction mechanisms involved in cardiac preconditioning: role of Ras-GTPase, Ca2+/calmodulin-dependent protein kinase II and epidermal growth factor receptor. Mol Cell Biochem. 2005; 268(1-2):175-83. DOI: 10.1007/s11010-005-3895-1. View

16.

Rajan S, Plant L, Rabin M, Butler M, Goldstein S . Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell. 2005; 121(1):37-47. DOI: 10.1016/j.cell.2005.01.019. View

17.

Cho C, Song W, Leitzell K, Teo E, Meleth A, Quick M . Rapid upregulation of alpha7 nicotinic acetylcholine receptors by tyrosine dephosphorylation. J Neurosci. 2005; 25(14):3712-23. PMC: 6725387. DOI: 10.1523/JNEUROSCI.5389-03.2005. View

18.

Besana A, Barbuti A, Tateyama M, Symes A, Robinson R, Feinmark S . Activation of protein kinase C epsilon inhibits the two-pore domain K+ channel, TASK-1, inducing repolarization abnormalities in cardiac ventricular myocytes. J Biol Chem. 2004; 279(32):33154-60. DOI: 10.1074/jbc.M403525200. View

19.

Zhou S, Zhang L, Sun W, Xiao F, Zhou Y, Li Y . Effects of monocarboxylic acid-derived Cl- channel blockers on depolarization-activated potassium currents in rat ventricular myocytes. Exp Physiol. 2007; 92(3):549-59. DOI: 10.1113/expphysiol.2007.037069. View

20.

Lakshman M, Xu L, Ananthanarayanan V, Cooper J, Takimoto C, Helenowski I . Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res. 2008; 68(6):2024-32. DOI: 10.1158/0008-5472.CAN-07-1246. View