TABLE 4

KV1.3 channels

Channel name KV1.31,2,3,4,5,6,7,8
Description Voltage-gated potassium channel, delayed rectifier
Other names MK3, MBK3, RCK3, hPCN3, HuK (III), HLK3, RGK5, KV3, HGK5, n-channel
Molecular information Human: 523aa, NM_002232, chr. 1p13.3,7,9 KCNA3, GeneID: 3738, PMID: 22512834
Mouse: 528aa, NM_008418, chr. 3
Rat: 525aa, NM_019270, chr. 2q34
Associated subunits KVβ, hDlg, β1 integrin, KChaP10,11,12
Functional assays Voltage-clamp
Current Type N voltage-gated potassium channel in lymphocytes3,4
Conductance 13pS4
Ion selectivity K+ (1) > Rb+ (0.77) > NH4+ (0.1) > Cs+ (0.02) > Na+ (<0.01)13
Activation Voltage, Va = -35 mV; ka = 6 mV; τn = 3 ms at 40 mV4,13
Inactivation C-type inactivation, Vh = -63 mV; kh = 7.7 mV; τh = 250 ms (40 mV)4
Activators None
Gating inhibitors None
Blockers 4-Aminopyridine (195 μM), tetraethyammonium (10 mM), charybdotoxin (3 nM), naltrexone (1 nM), MgTX (110 pM), kaliotoxin (650 pM), AgTX2 (200 pM), Pi1 (11 nM), Pi2 (50 pM), Pi3 (500 pM), HsTx1 (12 pM), ShK (11 pM), BgK (39 nM), ShK-Dap22 (52 pM), quinine (14 μM), diltiazem (60 μM), verapamil (6 μM), CP339818 (150 nM), UK78282 (200 nM), correolide (90 nM), sulfamidbenzamidoindane (100 nM), capsaicin (26 μM), resiniferatoxin (3 μM), nifedipine (5 μM), H37 (23 μM)14,15
Radioligands 125I-HgTx1-A19Y/Y37F mutant (0.1–0.25 pM); 125I-MgTx (0.3 pM)16,17
Channel distribution Brain (inferior colliculus > olfactory bulb, pons/medulla > midbrain, superior colliculus, corpus striatum, hippocampus, cerebral cortex), lung, islets, thymus, spleen, lymph node, fibroblasts, B lymphocytes, T lymphocytes, pre-B cells tonsils, macrophages, microglia, oligodendrocytes, osteoclasts, platelets, testis1,2,3,4,5,6,7,8,18,19,20,21
Physiological functions Regulation of membrane potential and calcium signaling in lymphocytes and oligodendrocytes14,21,22,23
Mutations and pathophysiology Not established
Pharmacological significance Therapeutic target for immunosuppressants; KV1.3 inhibitors suppress T-cell activation in vitro and delayed type hypersensitivity in vivo and have proven effective for multiple sclerosis in an animal24,25; KV1.3 expression is dramatically and exclusively increased in effector memory T cells
Comments Can coassemble with other KV1 family members in heteromultimers but not with members of other KV families; intronless coding region; mammalian Shaker-related family

  • aa, amino acids; chr., chromosome; MgTX, margatoxin; HgTX, hongotoxin; CP339818, N-[1-(phenylmethyl)-4(1H)-quinolinylidene]-1-pentamine monohydrochloride; UK78282, 4-[(diphenylmethoxy)methyl]-1-[3-(4-methoxyphenyl)propyl]-piperidine.

  • ↵1. Stuhmer W, Ruppersberg JP, Schroter KH, Sakmann B, Stocker M, Giese KP, Perschke A, Baumann A, and Pongs O (1989) Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain. EMBO J 8:3235-3244

  • ↵2. Chandy KG, Williams CB, Spencer RH, Aguilar BA, Ghanshani S, Tempel BL, and Gutman GA (1990) A family of three mouse potassium channel genes with intronless coding regions. Science (Wash DC) 247:973-975

  • ↵3. Douglass J, Osborne PB, Cai YC, Wilkinson M, Christie MJ, and Adelman JP (1990) Characterization and functional expression of a rat genomic DNA clone encoding a lymphocyte potassium channel. J Immunol 144:4841-4850

  • ↵4. Grissmer S, Dethlefs B, Wasmuth JJ, Goldin AL, Gutman GA, Cahalan MD, and Chandy KG (1990) Expression and chromosomal localization of a lymphocyte K+ channel gene. Proc Natl Acad Sci USA 87:9411-9415

  • ↵5. Philipson LH, Hice RE, Schaefer K, LaMendola J, Bell GI, Nelson DJ, and Steiner, DF (1991) Sequence and functional expression in Xenopus oocytes of a human insulinoma and islet potassium channel. Proc Natl Acad Sci USA 88:53-57

  • ↵6. Swanson R, Marshall J, Smith JS, Williams JB, Boyle MB, Folander K, Luneau CJ, Antanavage J, Oliva C, Buhrow SA, et al. (1990) Cloning and expression of cDNA, and genomic clones encoding three delayed rectifier potassium channels in rat brain. Neuron 4:929-939

  • ↵7. Attali B, Romey G, Honore E, Schmid-Alliana A, Mattei MG, Lesage F, Ricard P, Barhanin J, and Lazdunski M (1992) Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes. J Biol Chem 267:8650-8657

  • ↵8. Cai YC, Osborne PB, North RA, Dooley DC, and Douglass J (1992) Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel. DNA Cell Biol 11:163-172

  • ↵9. Folander K, Douglass J, and Swanson R (1994) Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1. Genomics 23:295-296

  • ↵10. McCormack T, McCormack K, Nadal MS, Vieira E, Ozaita A, and Rudy B (1999) The effects of Shaker β-subunits on the human lymphocyte K+ channel Kv1.3. J Biol Chem 274:20123-21126

  • ↵11. Hanada T, Lin L Chandy KG, Oh SS, and Chishti AH (1997) Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes. J Biol Chem 272:26899-26904

  • ↵12. Levite M, Cahalon L, Peretz A, Hershkoviz R, Sobko A, Ariel A, Desai R, Attali B, and Lider O (2000) Extracellular K+ and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and β1 integrins. J Exp Med 191:1167-1176

  • ↵13. Cahalan MD, Chandy KG, DeCoursey TE, and Gupta S (1985) A voltage-gated potassium channel in human T lymphocytes. J Physiol 358:197-237

  • ↵14. Grissmer S, Nguyen AN, Aiyar J, Hanson DC, Mather RJ, Gutman GA, Karmilowicz MJ, Auperin DD, and Chandy KG (1994) Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol Pharmacol 45:1227-1234

  • ↵15. Chandy KG, Cahalan MD, Pennington M, Norton RS, Wulff H, and Gutman GA (2001) Potassium channels in T lymphocytes: toxins to therapeutic immunosuppressants. Toxicon 39:1269-1276

  • ↵16. Koschak A, Bugianesi RM, Mitterdorfer J, Kaczorowski GJ, Garcia ML, and Knaus HG (1998) Subunit composition of brain voltage-gated potassium channels determined by hongotoxin-1, a novel peptide derived from Centruroides limbatus venom. J Biol Chem 273:2639-2644

  • ↵17. Koch RO, Wanner SG, Koschak A, Hanner M, Schwarzer C, Kaczorowski GJ, Slaughter RS, Garcia ML, and Knaus HG (1997) Complex subunit assembly of neuronal voltage-gated K+ channels: basis for high-affinity toxin interactions and pharmacology. J Biol Chem 272:27577-27581

  • ↵18. UniGene Cluster Hs0.169948 Homo sapiens

  • ↵19. Arkett SA, Dixon J, Yang JN, Sakai DD, Minkin C, and Sims SM (1994) Mammalian osteoclasts express a transient potassium channel with properties of Kv1.3. Receptors Channels 2:281-293

  • ↵20. DeCoursey TE, Kim SY, Silver MR, and Quandt FN (1996) Ion channel expression in PMA-differentiated human THP-1 macrophages. J Membr Biol 152:141-157

  • ↵21. Chittajallu R, Chen Y, Wang H, Yuan X, Ghiani CA, Heckman T, McBain CJ, and Gallo V (2002) Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G1/S phase progression of the cell cycle. Proc Natl Acad Sci USA 99:2350-2355

  • ↵22. Cahalan MD and Chandy KG (1997) Ion channels in the immune system as targets for immuno suppression. Curr Opin Biotechnol 8:749-756

  • ↵23. Cahalan MD, Wulff H, and Chandy KG (2001) Molecular properties and physiological roles of ion channels in the immune system. J Clin Immunol 21:235-252

  • ↵24. Koo GC, Blake JT, Talento A, Nguyen M, Lin S, Sirotina A, Shah K, Mulvany K, Hora D Jr, Cunningham P, et al (1997) Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. J Immunol 158:5120-5128

  • ↵25. Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M, Bernard D, Cahalan MD, Chandy KG, and Beraud E (2001) Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proc Natl Acad Sci USA 98:13942-13947