Two P domain potassium channels | Ion channels | IUPHAR/BPS Guide to PHARMACOLOGY

Two P domain potassium channels C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two P domain, or K_2P channels (and not two-pore channels). Some of the K_2P subunits can form heterodimers across subfamilies (e.g. K_2P3.1 with K_2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, below, is based on similarities in both structural and functional properties within subfamilies.

Channels and Subunits

K_2P1.1 C Show summary »« Hide summary More detailed page

Target Id	513
Nomenclature	K_2P1.1
Previous and unofficial names	TWIK-1 \| hOHO \| DPK \| potassium channel, subfamily K, member 1 \| potassium channel, two pore domain subfamily K, member 1 \| potassium channel
Genes	KCNK1 (Hs), Kcnk1 (Mm), Kcnk1 (Rn)
Ensembl ID	ENSG00000135750 (Hs), ENSMUSG00000033998 (Mm), ENSRNOG00000019937 (Rn)
UniProtKB AC	O00180 (Hs), O08581 (Mm), Q9Z2T2 (Rn)
Functional characteristics	Background current
Comment	K_2P1.1 is inhibited by acid pH_o external acidification with a pK_a ~6.7 [23]. K_2P1 forms heterodimers with K_2P3 and K_2P9 [24].

K_2P2.1 C Show summary »« Hide summary More detailed page

Target Id

514

Nomenclature

K_2P2.1

Previous and unofficial names

TREK-1 | TPKC1 | arachidonic acid sensitive tandem pore domain potassium channel | potassium channel, two pore domain subfamily K, member 2 | potassium channel

Genes

KCNK2 (Hs), Kcnk2 (Mm), Kcnk2 (Rn)

Ensembl ID

ENSG00000082482 (Hs), ENSMUSG00000037624 (Mm), ENSRNOG00000002653 (Rn)

UniProtKB AC

O95069 (Hs), P97438 (Mm)

Endogenous activators

arachidonic acid pEC₅₀ 5.0 (studied at 1-10 µM) [22]

Activators

chloroform Concentration range: 8x10^-3 M (studied at 1-5 mM) [21]

halothane (studied at 1-5 mM) [21]

isoflurane (studied at 1-5 mM) [21]

Inhibitors

norfluoxetine pIC₅₀ 5.1 [12]

Functional characteristics

Background current

Comment

K_2P2.1 is also activated by membrane stretch, heat and acid pH_i [18,20]. K_2P2 can heterodimerize with K_2P4 [2] and K_2P10 [15].

K_2P3.1 C Show summary »« Hide summary More detailed page

Target Id

515

Nomenclature

K_2P3.1

Previous and unofficial names

Genes

KCNK3 (Hs), Kcnk3 (Mm), Kcnk3 (Rn)

Ensembl ID

ENSG00000171303 (Hs), ENSMUSG00000049265 (Mm), ENSRNOG00000009790 (Rn)

UniProtKB AC

O14649 (Hs), O35111 (Mm), O54912 (Rn)

Activators

halothane (studied at 1-10 mM)

Channel blockers

anandamide pIC₅₀ ~6.2 [19]

R-(+)-methanandamide pIC₅₀ ~6.2 [19]

Functional characteristics

Background current

Comment

Knock-out of the kcnk3 gene leads to a prolonged QT interval in mice [6] and disrupted development of the adrenal cortex [9]. K_2P3.1 is inhibited by acid pH_o with a pK_a of 6.4 [16]. K_2P3 forms heterodimers with K_2P1 [24] and K_2P9 [5].

K_2P4.1 C Show summary »« Hide summary More detailed page

Target Id

516

Nomenclature

K_2P4.1

Previous and unofficial names

TRAAK | KT4.1 | potassium channel, subfamily K, member 4 | potassium channel, two pore domain subfamily K, member 4 | potassium channel

Genes

KCNK4 (Hs), Kcnk4 (Mm), Kcnk4 (Rn)

Ensembl ID

ENSG00000182450 (Hs), ENSMUSG00000024957 (Mm), ENSRNOG00000021140 (Rn)

UniProtKB AC

Q9NYG8 (Hs), O88454 (Mm)

Endogenous activators

arachidonic acid (studied at 1-10 µM) [8]

Activators

riluzole (studied at 1-100 µM) [7]

Functional characteristics

Background current

Comment

K_2P4 is activated by membrane stretch [17], and increased temperature (~12 to 20-fold between 17 and 40°C [10]) and can heterodimerize with K_2P2 [2].

K_2P5.1 C Show summary »« Hide summary More detailed page

Target Id	517
Nomenclature	K_2P5.1
Previous and unofficial names	TASK-2 \| potassium channel subfamily K member 5 \| potassium channel, two pore domain subfamily K, member 5 \| potassium channel
Genes	KCNK5 (Hs), Kcnk5 (Mm), Kcnk5 (Rn)
Ensembl ID	ENSG00000164626 (Hs), ENSMUSG00000023243 (Mm), ENSRNOG00000047005 (Rn)
UniProtKB AC	O95279 (Hs)
Functional characteristics	Background current
Comment	K_2P5.1 is activated by alkaline pH_o [27]. Knockout of the kcnk5 gene in mice is associated with metabolic acidosis, hyponatremia and hypotension due to impaired bicarbonate handling in the kidney [31], as well as deafness [4]. The T108P mutation is associated with Balkan Endemic Nephropathy in humans [30].

K_2P6.1 C Show summary »« Hide summary More detailed page

Target Id	518
Nomenclature	K_2P6.1
Previous and unofficial names	TOSS \| potassium channel subfamily K member 6 (TWIK-2) \| potassium channel, two pore domain subfamily K, member 6 \| potassium inwardly-rectifying channel
Genes	KCNK6 (Hs), Kcnk6 (Mm), Kcnk6 (Rn)
Ensembl ID	ENSG00000099337 (Hs), ENSMUSG00000046410 (Mm), ENSRNOG00000020598 (Rn)
UniProtKB AC	Q9Y257 (Hs)
Functional characteristics	Unknown

K_2P7.1 C Show summary »« Hide summary More detailed page

Target Id	519
Nomenclature	K_2P7.1
Previous and unofficial names	kcnk8 \| Knot \| Mlk3 \| potassium channel, subfamily K, member 7 \| potassium channel, two pore domain subfamily K, member 7 \| potassium channel
Genes	KCNK7 (Hs), Kcnk7 (Mm), Kcnk7 (Rn)
Ensembl ID	ENSG00000173338 (Hs), ENSMUSG00000024936 (Mm), ENSRNOG00000020784 (Rn)
UniProtKB AC	Q9Y2U2 (Hs), Q9Z2T1 (Mm), D4A806 (Rn)
Functional characteristics	Unknown

K_2P9.1 C Show summary »« Hide summary More detailed page

Target Id

520

Nomenclature

K_2P9.1

Previous and unofficial names

Genes

KCNK9 (Hs), Kcnk9 (Mm), Kcnk9 (Rn)

Ensembl ID

ENSG00000169427 (Hs), ENSMUSG00000036760 (Mm), ENSRNOG00000009265 (Rn)

UniProtKB AC

Q9NPC2 (Hs), Q3LS21 (Mm), Q9ES08 (Rn)

Activators

halothane (studied at 1-5 mM) [29]

Inhibitors

anandamide (studied at 1-10 µM) [26]

R-(+)-methanandamide (studied at 1-10 µM) [26]

Functional characteristics

Background current

Comment

K_2P9.1 is also inhibited by acid pH_o with a pK_a of ~6 [26]. Imprinting of the KCNK9 gene is associated with Birk Barel syndrome [1]. K_2P9 can form heterodimers with K_2P1 [24] or K_2P3 [5].

K_2P10.1 C Show summary »« Hide summary More detailed page

Target Id

521

Nomenclature

K_2P10.1

Previous and unofficial names

TREK-2 | potassium channel, two pore domain subfamily K, member 10 | potassium channel

Genes

KCNK10 (Hs), Kcnk10 (Mm), Kcnk10 (Rn)

Ensembl ID

ENSG00000100433 (Hs), ENSMUSG00000033854 (Mm), ENSRNOG00000003813 (Rn)

UniProtKB AC

P57789 (Hs), Q9JIS4 (Rn)

Endogenous activators

arachidonic acid (studied at 1-10 µM) [14]

Activators

halothane (studied at 1-5 mM) [14]

Functional characteristics

Background current

Comment

K_2P10.1 is also activated by membrane stretch [14] and can heterodimerize with K_2P2 [15].

K_2P12.1 C Show summary »« Hide summary More detailed page

Target Id	522
Nomenclature	K_2P12.1
Previous and unofficial names	THIK-2 \| tandem pore domain halothane-inhibited potassium channel 2 \| tandem pore domain potassium channel THIK-2 \| mntk1 \| potassium channel, two pore domain subfamily K, member 12 \| potassium channel
Genes	KCNK12 (Hs), Kcnk12 (Mm), Kcnk12 (Rn)
Ensembl ID	ENSG00000184261 (Hs), ENSMUSG00000050138 (Mm), ENSRNOG00000016110 (Rn)
UniProtKB AC	Q9HB15 (Hs), Q9ERS1 (Rn)
Functional characteristics	Does not function as a homodimer [25] but can form a functional heterodimer with K_2P13 [3].

K_2P13.1 C Show summary »« Hide summary More detailed page

Target Id

523

Nomenclature

K_2P13.1

Previous and unofficial names

THIK-1 | prdx1 | tandem pore domain halothane-inhibited potassium channel 1 | potassium channel, two pore domain subfamily K, member 13 | potassium channel

Genes

KCNK13 (Hs), Kcnk13 (Mm), Kcnk13 (Rn)

Ensembl ID

ENSG00000152315 (Hs), ENSMUSG00000045404 (Mm), ENSRNOG00000003926 (Rn)

UniProtKB AC

Q9HB14 (Hs), Q8R1P5 (Mm), Q9ERS0 (Rn)

Inhibitors

halothane (studied at ~5 mM) [3]

Functional characteristics

Background current

Comment

Forms a heterodimer with K_2P12 [3].

K_2P15.1 C Show summary »« Hide summary More detailed page

Target Id	524
Nomenclature	K_2P15.1
Previous and unofficial names	KT3.3 \| KCNK14 \| potassium channel subfamily K member 15 (TASK-5) \| TWIK-related acid-sensitive K(+) channel 5 \| acid-sensitive potassium channel protein TASK-5 \| KCNK11 \| potassium channel, subfamily K, member 15 \| potassium channel, two pore domain subfamily K, member 15 \| potassium channel
Genes	KCNK15 (Hs), Kcnk15 (Mm), Kcnk15 (Rn)
Ensembl ID	ENSG00000124249 (Hs), ENSMUSG00000035238 (Mm), ENSRNOG00000010816 (Rn)
UniProtKB AC	Q9H427 (Hs), Q8R5I0 (Rn)
Functional characteristics	Unknown

K_2P16.1 C Show summary »« Hide summary More detailed page

Target Id	525
Nomenclature	K_2P16.1
Previous and unofficial names	TALK1 \| potassium channel, two pore domain subfamily K, member 16 \| potassium channel
Genes	KCNK16 (Hs), Kcnk16 (Mm), Kcnk16 (Rn)
Ensembl ID	ENSG00000095981 (Hs), ENSMUSG00000023387 (Mm), ENSRNOG00000006422 (Rn)
UniProtKB AC	Q96T55 (Hs)
Functional characteristics	Background current
Comment	K_2P16.1 current is increased by alkaline pH_o with a pK_a of 7.8 [11].

K_2P17.1 C Show summary »« Hide summary More detailed page

Target Id	526
Nomenclature	K_2P17.1
Previous and unofficial names	TALK2 \| TASK4 \| potassium channel, subfamily K, member 17 \| potassium channel, two pore domain subfamily K, member 17
Genes	KCNK17 (Hs)
Ensembl ID	ENSG00000124780 (Hs)
UniProtKB AC	Q96T54 (Hs)
Functional characteristics	Background current
Comment	K_2P17.1 current is increased by alkaline pH_o with a pK_a of 8.8 [11].

K_2P18.1 C Show summary »« Hide summary More detailed page

Target Id

527

Nomenclature

K_2P18.1

Previous and unofficial names

Genes

KCNK18 (Hs), Kcnk18 (Mm), Kcnk18 (Rn)

Ensembl ID

ENSG00000186795 (Hs), ENSMUSG00000040901 (Mm), ENSRNOG00000032706 (Rn)

UniProtKB AC

Q7Z418 (Hs), Q6VV64 (Mm), Q6Q1P3 (Rn)

Endogenous inhibitors

arachidonic acid (studied at 10-50 µM) [28]

Functional characteristics

Background current

Comment

A frame-shift mutation (F139WfsX24) in the KCNK18 gene, is associated with migraine with aura in humans [13].

Comments

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References

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1. Barel O, Shalev SA, Ofir R, Cohen A, Zlotogora J, Shorer Z, Mazor G, Finer G, Khateeb S, Zilberberg N et al.. (2008) Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am. J. Hum. Genet., 83 (2): 193-9. [PMID:18678320]

2. Blin S, Ben Soussia I, Kim EJ, Brau F, Kang D, Lesage F, Bichet D. (2016) Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties. Proc. Natl. Acad. Sci. U.S.A., 113 (15): 4200-5. [PMID:27035965]

3. Blin S, Chatelain FC, Feliciangeli S, Kang D, Lesage F, Bichet D. (2014) Tandem pore domain halothane-inhibited K+ channel subunits THIK1 and THIK2 assemble and form active channels. J. Biol. Chem., 289 (41): 28202-12. [PMID:25148687]

4. Cazals Y, Bévengut M, Zanella S, Brocard F, Barhanin J, Gestreau C. (2015) KCNK5 channels mostly expressed in cochlear outer sulcus cells are indispensable for hearing. Nat Commun, 6: 8780. [PMID:26549439]

5. Czirják G, Enyedi P. (2002) Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits. J. Biol. Chem., 277 (7): 5426-32. [PMID:11733509]

6. Decher N, Wemhöner K, Rinné S, Netter MF, Zuzarte M, Aller MI, Kaufmann SG, Li XT, Meuth SG, Daut J et al.. (2011) Knock-out of the potassium channel TASK-1 leads to a prolonged QT interval and a disturbed QRS complex. Cell. Physiol. Biochem., 28 (1): 77-86. [PMID:21865850]

7. Duprat F, Lesage F, Patel AJ, Fink M, Romey G, Lazdunski M. (2000) The neuroprotective agent riluzole activates the two P domain K(+) channels TREK-1 and TRAAK. Mol. Pharmacol., 57 (5): 906-12. [PMID:10779373]

8. Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M, Lazdunski M. (1998) A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids. EMBO J., 17 (12): 3297-308. [PMID:9628867]

9. Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C, Schweda F, El Wakil A, Lalli E, Guy N, Mengual R et al.. (2008) Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. EMBO J., 27 (1): 179-87. [PMID:18034154]

10. Kang D, Choe C, Kim D. (2005) Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. J. Physiol. (Lond.), 564 (Pt 1): 103-16. [PMID:15677687]

11. Kang D, Kim D. (2004) Single-channel properties and pH sensitivity of two-pore domain K+ channels of the TALK family. Biochem. Biophys. Res. Commun., 315 (4): 836-44. [PMID:14985088]

12. Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A. (2005) Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br. J. Pharmacol., 144 (6): 821-9. [PMID:15685212]

13. Lafrenière RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenière F, McLaughlan S, Dubé MP et al.. (2010) A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat. Med., 16 (10): 1157-60. [PMID:20871611]

14. Lesage F, Terrenoire C, Romey G, Lazdunski M. (2000) Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J. Biol. Chem., 275 (37): 28398-405. [PMID:10880510]

15. Levitz J, Royal P, Comoglio Y, Wdziekonski B, Schaub S, Clemens DM, Isacoff EY, Sandoz G. (2016) Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels. Proc. Natl. Acad. Sci. U.S.A., 113 (15): 4194-9. [PMID:27035963]

16. Lopes CM, Gallagher PG, Buck ME, Butler MH, Goldstein SA. (2000) Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3. J. Biol. Chem., 275 (22): 16969-78. [PMID:10748056]

17. Maingret F, Fosset M, Lesage F, Lazdunski M, Honoré E. (1999) TRAAK is a mammalian neuronal mechano-gated K+ channel. J. Biol. Chem., 274 (3): 1381-7. [PMID:9880510]

18. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honoré E. (2000) TREK-1 is a heat-activated background K(+) channel. EMBO J., 19 (11): 2483-91. [PMID:10835347]

19. Maingret F, Patel AJ, Lazdunski M, Honoré E. (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. EMBO J., 20 (1-2): 47-54. [PMID:11226154]

20. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honoré E. (1999) Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. J. Biol. Chem., 274 (38): 26691-6. [PMID:10480871]

21. Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M. (1999) Inhalational anesthetics activate two-pore-domain background K+ channels. Nat. Neurosci., 2 (5): 422-6. [PMID:10321245]

22. Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M. (1998) A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J., 17 (15): 4283-90. [PMID:9687497]

23. Plant LD, Dementieva IS, Kollewe A, Olikara S, Marks JD, Goldstein SA. (2010) One SUMO is sufficient to silence the dimeric potassium channel K2P1. Proc. Natl. Acad. Sci. U.S.A., 107 (23): 10743-8. [PMID:20498050]

24. Plant LD, Zuniga L, Araki D, Marks JD, Goldstein SA. (2012) SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons. Sci Signal, 5 (251): ra84. [PMID:23169818]

25. Rajan S, Wischmeyer E, Karschin C, Preisig-Müller R, Grzeschik KH, Daut J, Karschin A, Derst C. (2001) THIK-1 and THIK-2, a novel subfamily of tandem pore domain K+ channels. J. Biol. Chem., 276 (10): 7302-11. [PMID:11060316]

26. Rajan S, Wischmeyer E, Xin Liu G, Preisig-Müller R, Daut J, Karschin A, Derst C. (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. J. Biol. Chem., 275 (22): 16650-7. [PMID:10747866]

27. Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, Lazdunski M. (1998) Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney. J. Biol. Chem., 273 (47): 30863-9. [PMID:9812978]

28. Sano Y, Inamura K, Miyake A, Mochizuki S, Kitada C, Yokoi H, Nozawa K, Okada H, Matsushime H, Furuichi K. (2003) A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. J. Biol. Chem., 278 (30): 27406-12. [PMID:12754259]

29. Talley EM, Bayliss DA. (2002) Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action. J. Biol. Chem., 277 (20): 17733-42. [PMID:11886861]

30. Toncheva D, Mihailova-Hristova M, Vazharova R, Staneva R, Karachanak S, Dimitrov P, Simeonov V, Ivanov S, Balabanski L, Serbezov D et al.. (2014) NGS nominated CELA1, HSPG2, and KCNK5 as candidate genes for predisposition to Balkan endemic nephropathy. Biomed Res Int, 2014: 920723. [PMID:24949484]

31. Warth R, Barrière H, Meneton P, Bloch M, Thomas J, Tauc M, Heitzmann D, Romeo E, Verrey F, Mengual R, Guy N, Bendahhou S, Lesage F, Poujeol P, Barhanin J. (2004) Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. Proc. Natl. Acad. Sci. U.S.A., 101 (21): 8215-20. [PMID:15141089]

NC-IUPHAR subcommittee and family contributors

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Subcommittee members:

Steve A.N. Goldstein (Chairperson)
Department of Biochemistry
Brandeis University
Waltham
MA 02453
USA

Leigh D. Plant
Research Associate Professor
Department of Pharmaceutical Sciences
Northeastern University, School of Pharmacy
Bouvé College of Health Sciences
360 Huntington Avenue
Boston, MA 02115

Other contributors:

Douglas A. Bayliss
Department of Pharmacology
University of Virginia Health System
Charlottesville
VA 22908
USA

Gábor Czirják
Department of Physiology
Semmelweis University
Budapest
Hungary

Péter Enyedi
Department of Physiology
Semmelweis University
Budapest
Hungary

Florian Lesage
CNRS UMR 7275 Université de Nice
Valbonne
France

Daniel L. Minor, Jr.
Cardiovascular Research Institute
Departments of Biochemistry & Biophysics
and Cellular & Molecular Pharmacology
California Institute for Quantitative Biomedical Research
Kavli Institute for Fundamental Neuroscience
University of California, San Francisco
CA, U.S.A.

Francisco Sepúlveda
Centro de Estudios Científicos
Valdivia
Chile

How to cite this family page

Database page citation:

Douglas A. Bayliss, Gábor Czirják, Péter Enyedi, Steve A.N. Goldstein, Florian Lesage, Daniel L. Minor, Jr., Leigh D. Plant, Francisco Sepúlveda. Two P domain potassium channels. Accessed on 17/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=79.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Striessnig J, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Voltage-gated ion channels. Br J Pharmacol. 174 Suppl 1: S160-S194.