Inhibitory Actions of the Phosphatidylinositol 3-kinase Inhibitor LY294002 on the Human Kv1.5 Channel

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2009 Jan 22

PMID 19154427

Citations 10

Authors

J Wu

W-G Ding

H Matsuura

K Tsuji

W-J Zang

M Horie

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Kv1.5 channels conduct the ultra-rapid delayed rectifier potassium current (I(Kur)), and in humans, Kv1.5 channels are highly expressed in cardiac atria but are scarce in ventricles. Pharmacological blockade of human Kv1.5 (hKv1.5) has been regarded as effective for prevention and treatment of re-entry-based atrial tachyarrhythmias. Here we examined blockade of hKv1.5 channels by LY294002, a well-known inhibitor of phosphatidylinositol 3-kinase (PI3K).

Experimental Approach: hKv1.5 channels were heterologously expressed in Chinese hamster ovary cells. Effects of LY294002 on wild-type and mutant (T462C, H463C, T480A, R487V, A501V, I502A, I508A, L510A and V516A) hKv1.5 channels were examined by using the whole-cell patch-clamp method.

Key Results: LY294002 rapidly and reversibly inhibited hKv1.5 current in a concentration-dependent manner (IC(50) of 7.9 micromol.L(-1)). In contrast, wortmannin, a structurally distinct inhibitor of PI3K, had little inhibitory effect on hKv1.5 current. LY294002 block of hKv1.5 current developed with time during depolarizing voltage-clamp steps, and this blockade was also voltage-dependent with a steep increase over the voltage range for channel openings. The apparent binding (k(+1)) and unbinding (k(-1)) rate constants were calculated to be 1.6 micromol.L(-1) (-1).s(-1) and 5.7 s(-1) respectively. Inhibition by LY294002 was significantly reduced in several hKv1.5 mutant channels: T480A, R487V, I502A, I508A, L510A and V516A.

Conclusions And Implications: LY294002 acts directly on hKv1.5 currents as an open channel blocker, independently of its effects on PI3K activity. Amino acid residues located in the pore region (Thr480, Arg487) and the S6 segment (Ile502, Ile508, Leu510, Val516) appear to constitute potential binding sites for LY294002.

Citing Articles

Open channel block of Kv1.5 channels by HMQ1611.

Dong C, Li J, Ding W, Ueda R, Xie X, Wu J Front Pharmacol. 2022; 13:965086.

PMID: 36188606 PMC: 9524145. DOI: 10.3389/fphar.2022.965086.

Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects.

Qin W, Li Y, Tong J, Wu J, Zhao D, Li H Front Mol Biosci. 2022; 8:805594.

PMID: 35141279 PMC: 8819089. DOI: 10.3389/fmolb.2021.805594.

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5.

Zhao Z, Ruan S, Ma X, Feng Q, Xie Z, Nie Z Biomolecules. 2019; 10(1).

PMID: 31861703 PMC: 7022446. DOI: 10.3390/biom10010010.

Regulation of human cardiac Kv1.5 channels by extracellular acidification.

Wang S, Ding W, Bai J, Toyoda F, Wei M, Matsuura H Pflugers Arch. 2016; 468(11-12):1885-1894.

PMID: 27796577 DOI: 10.1007/s00424-016-1890-x.

Blockade of Kv1.5 channels by the antidepressant drug sertraline.

Lee H, Hahn S, Choi B Korean J Physiol Pharmacol. 2016; 20(2):193-200.

PMID: 26937216 PMC: 4770110. DOI: 10.4196/kjpp.2016.20.2.193.

References

Vos M . Atrial-specific drugs: the way to treat atrial fibrillation?. J Cardiovasc Electrophysiol. 2004; 15(12):1451-2. DOI: 10.1046/j.1540-8167.2004.04569.x. View

Valenzuela C, Delpon E, Franqueza L, Gay P, Perez O, Tamargo J . Class III antiarrhythmic effects of zatebradine. Time-, state-, use-, and voltage-dependent block of hKv1.5 channels. Circulation. 1996; 94(3):562-70. DOI: 10.1161/01.cir.94.3.562. View

Powis G, Bonjouklian R, Berggren M, Gallegos A, Abraham R, Ashendel C . Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 1994; 54(9):2419-23. View

Crijns H, Van Gelder I, Walfridsson H, Kulakowski P, Ronaszeki A, Dedek V . Safe and effective conversion of persistent atrial fibrillation to sinus rhythm by intravenous AZD7009. Heart Rhythm. 2006; 3(11):1321-31. DOI: 10.1016/j.hrthm.2006.06.035. View

Knight Z, Chiang G, Alaimo P, Kenski D, Ho C, Coan K . Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. Bioorg Med Chem. 2004; 12(17):4749-59. DOI: 10.1016/j.bmc.2004.06.022. View

Kristof A, Pacheco-Rodriguez G, Schremmer B, Moss J . LY303511 (2-piperazinyl-8-phenyl-4H-1-benzopyran-4-one) acts via phosphatidylinositol 3-kinase-independent pathways to inhibit cell proliferation via mammalian target of rapamycin (mTOR)- and non-mTOR-dependent mechanisms. J Pharmacol Exp Ther. 2005; 314(3):1134-43. DOI: 10.1124/jpet.105.083550. View

Regan C, Stump G, Wallace A, Anderson K, McIntyre C, Liverton N . In vivo cardiac electrophysiologic and antiarrhythmic effects of an isoquinoline IKur blocker, ISQ-1, in rat, dog, and nonhuman primate. J Cardiovasc Pharmacol. 2007; 49(4):236-45. DOI: 10.1097/FJC.0b013e3180325b2a. View

Herrera D, Mamarbachi A, Simoes M, Parent L, Sauve R, Wang Z . A single residue in the S6 transmembrane domain governs the differential flecainide sensitivity of voltage-gated potassium channels. Mol Pharmacol. 2005; 68(2):305-16. DOI: 10.1124/mol.104.009506. View

Brendel J, Peukert S . Blockers of the Kv1.5 channel for the treatment of atrial arrhythmias. Curr Med Chem Cardiovasc Hematol Agents. 2004; 1(3):273-87. DOI: 10.2174/1568016033477441. View

10.

Fedida D, Wible B, Wang Z, Fermini B, FAUST F, Nattel S . Identity of a novel delayed rectifier current from human heart with a cloned K+ channel current. Circ Res. 1993; 73(1):210-6. DOI: 10.1161/01.res.73.1.210. View

11.

Perchenet L . Characterization of mibefradil block of the human heart delayed rectifier hKv1.5. J Pharmacol Exp Ther. 2000; 295(2):771-8. View

12.

Snyders D, Yeola S . Determinants of antiarrhythmic drug action. Electrostatic and hydrophobic components of block of the human cardiac hKv1.5 channel. Circ Res. 1995; 77(3):575-83. DOI: 10.1161/01.res.77.3.575. View

13.

Chugh S, Blackshear J, Shen W, Hammill S, Gersh B . Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol. 2001; 37(2):371-8. DOI: 10.1016/s0735-1097(00)01107-4. View

14.

Decher N, Kumar P, Gonzalez T, Renigunta V, Sanguinetti M . Structural basis for competition between drug binding and Kvbeta 1.3 accessory subunit-induced N-type inactivation of Kv1.5 channels. Mol Pharmacol. 2005; 68(4):995-1005. DOI: 10.1124/mol.105.011668. View

15.

Gamper N, Fillon S, Huber S, Feng Y, Kobayashi T, Cohen P . IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Arch. 2002; 443(4):625-34. DOI: 10.1007/s00424-001-0741-5. View

16.

Snyders D, Tamkun M, Bennett P . A rapidly activating and slowly inactivating potassium channel cloned from human heart. Functional analysis after stable mammalian cell culture expression. J Gen Physiol. 1993; 101(4):513-43. PMC: 2216772. DOI: 10.1085/jgp.101.4.513. View

17.

Strutz-Seebohm N, Gutcher I, Decher N, Steinmeyer K, Lang F, Seebohm G . Comparison of potent Kv1.5 potassium channel inhibitors reveals the molecular basis for blocking kinetics and binding mode. Cell Physiol Biochem. 2007; 20(6):791-800. DOI: 10.1159/000110439. View

18.

Decher N, Pirard B, Bundis F, Peukert S, Baringhaus K, Busch A . Molecular basis for Kv1.5 channel block: conservation of drug binding sites among voltage-gated K+ channels. J Biol Chem. 2003; 279(1):394-400. DOI: 10.1074/jbc.M307411200. View

19.

Vlahos C, Matter W, Hui K, Brown R . A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994; 269(7):5241-8. View

20.

Yeola S, Rich T, Uebele V, Tamkun M, Snyders D . Molecular analysis of a binding site for quinidine in a human cardiac delayed rectifier K+ channel. Role of S6 in antiarrhythmic drug binding. Circ Res. 1996; 78(6):1105-14. DOI: 10.1161/01.res.78.6.1105. View