The role of channel Kv1.3 in the development of rheumatoid arthritis
Keywords:
Rheumatoid arthritis, autoimmune disease, signaling pathway, potassium channelAbstract
Rheumatoid arthritis is an autoimmune disease characterized by an inflammatory process in the joints. The etiology is not well known, but multiple risk factors such as genetics, infections, and immunoregulation disorders may be involved. The cellular and molecular mechanisms include recruitment of certain types of cells and expression of proinflammatory cytokines in the surroundings. However, certain molecules may have an additional role in the development of the pathogenesis. One of these novel markers is the channel Kv1.3; this protein regulates potassium ion fluxes and activates signaling pathways in several cell types, including T-cells.
Lymphocytes are key elements in the progression of RA; they induce proinflammatory cytokines in affected tissue. Kv1.3 is highly expressed in regulatory T lymphocytes related to autoimmune diseases; therefore, in recent years, this channel has been suggested as a potential target for therapeutics. Several inhibitors are developed and isolated from natural sources that provide a good approach to modulate pathologic immune responses mediated by T-cells targeting Kv1.3.
References
Fishman P, Bar-Yehuda S. Rheumatoid arthritis: history, molecular mechanisms and therapeutic applications. In: Borea PA, editor. A3 adenosine receptors from cell biology to pharmacology and therapeutics. Netherlands: Springer; 2010. pp. 291-298.
AARDA. Autoimmune Statistics. 2014 [cited 29-09- 2014]. Available from: http://www.aarda.org/autoim- mune-information/autoimmune-statistics/.
Cardiel MH, Díaz-Borjón A, Vázquez del Mercado Espi-
nosa M, Gámez-Nava JI, Barile Fabris LA, Pacheco Tena
C et al. Update of the Mexican College of Rheumatology
guidelines for the pharmacologic treatment of rheumatoid
arthritis. Reumatol Clin. 2014; 10 (4): 227-240.
Mendoza-Vázquez G, Rocha-Muñoz AD, Guerra-Soto A, Ramírez-Villafaña M, González-Sánchez AG, Gámez- Nava JI et al. Artritis reumatoide y dislipidemias. El
Residente. 2013; 8 (1): 12-22.
Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh
KL et al. A molecular basis for the association of the
HLA-DRB1 locus, citrullination, and rheumatoid arthritis.
J Exp Med. 2013; 210 (12): 2569-2582.
Winchester R. Genetic determination of susceptibility
and severity in rheumatoid arthritis. Ann Intern Med.
; 117 (10): 869-871.
Li G, Shi F, Liu J, Li Y. The effect of CTLA-4 A49G poly-
morphism on rheumatoid arthritis risk: a meta-analysis.
Diagn Pathol. 2014; 9: 157.
Shakiba E, Tavilani H, Goodarzi MT, Kiani A, Pour-
motabbed T, Vaisi-Raygani A. The ITGAV-rs3911238 polymorphism is associated with disease activity in rheumatoid arthritis. Iran J Allergy Asthma Immunol. 2014; 13 (5): 356-363.
Okamoto H, Hoshi D, Kiire A, Yamanaka H, Kamatani N. Molecular targets of rheumatoid arthritis. Inflamm Allergy Drug Targets. 2008; 7 (1): 53-66.
Malemud CJ. Intracellular signaling pathways in rheu- matoid arthritis. J Clin Cell Immunol. 2013; 4: 160.
McInnes IB, Schett G. Cytokines in the pathogenesis
of rheumatoid arthritis. Nat Rev Immunol. 2007; 7 (6):
-442.
Roeleveld DM, Koenders MI. The role of the Th17
cytokines IL-17 and IL-22 in rheumatoid arthritis patho- genesis and developments in cytokine immunotherapy. Cytokine. 2015; 74 (1): 101-107.
MacKinnon R. Determination of the subunit stoichiom- etry of a voltage-activated potassium channel. Nature. 1991; 350 (6315): 232-235.
Li Y, Wang P, Xu J, Desir GV. Voltage-gated potassium channel Kv1.3 regulates GLUT4 trafficking to the plasma membrane via a Ca2+-dependent mechanism. Am J Physiol Cell Physiol. 2006; 290 (2): C345-C351.
Hu L, Wang T, Gocke AR, Nath A, Zhang H, Margolick JB et al. Blockade of Kv1.3 potassium channels inhibits differentiation and granzyme B secretion of human CD8+ T effector memory lymphocytes. PLoS One. 2013; 8 (1): e54267.
Levitan ES, Takimoto K. Surface expression of Kv1 voltage-gated K+ channels is governed by a C-terminal motif. Trends Cardiovasc Med. 2000; 10 (7): 317-320.
XuJ,WangP,LiY,LiG,KaczmarekLK,WuYetal. The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity. Proc Natl Acad Sci U S A. 2004; 101 (9): 3112-3117.
Comes N, Bielanska J, Vallejo-Gracia A, Serrano- Albarras A, Marruecos L, Gomez D et al. The voltage- dependent K(+) channels Kv1.3 and Kv1.5 in human
cancer. Front Physiol. 2013; 4:283
Airmid. Kv1.3 Potassium Channel. 2014. Available from:
http://www.airmid.com/kv-potassium-channel.html.
Panyi G, Varga Z, Gaspar R. Ion channels and lympho- cyte activation. Immunol Lett. 2004; 92 (1-2): 55-66.
HouP,ZhangR,LiuY,FengJ,WangW,WuYetal. Physiological role of Kv1.3 channel in T lymphocyte cell investigated quantitatively by kinetic modeling. PLoS One. 2014; 9 (3): e89975.
Imboden JB, Weiss A. The T-cell antigen receptor regulates sustained increases in cytoplasmic free Ca2+
through extracellular Ca2+ influx and ongoing intracel-
lular Ca2+ mobilization. Biochem J. 1987; 247 (3): 695-
Weiss A, Imboden J, Hardy K, Stobo J. The role of the antigen receptor/T3 complex in T-cell activation. Adv Exp Med Biol. 1987; 213: 45-49.
Panyi G, Vamosi G, Bacso Z, Bagdany M, Bodnar A, Varga Z et al. Kv1.3 potassium channels are localized in the immunological synapse formed between cytotoxic and target cells. Proc Natl Acad Sci U S A. 2004; 101 (5): 1285-1290.
Panyi G, Bagdany M, Bodnar A, Vamosi G, Szentesi G, Jenei A et al. Colocalization and nonrandom distribution of Kv1.3 potassium channels and CD3 molecules in the plasma membrane of human T lymphocytes. Proc Natl Acad Sci U S A. 2003; 100 (5): 2592-2597.
Szilagyi O, Boratko A, Panyi G, Hajdu P. The role of PSD-95 in the rearrangement of Kv1.3 channels to the immunological synapse. Pflugers Arch. 2013 ;465 (9): 1341-1353.
Lewis RS. Calcium signaling mechanisms in T lympho- cytes. Annu Rev Immunol. 2001; 19: 497-521.
Lin CS, Boltz RC, Blake JT, Nguyen M, Talento A, Fischer PA et al. Voltage-gated potassium channels regulate calcium-dependent pathways involved in hu- man T lymphocyte activation. J Exp Med. 1993; 177 (3): 637-645.
Nicolaou SA, Neumeier L, Steckly A, Kucher V, Takimoto K, Conforti L. Localization of Kv1.3 channels in the im- munological synapse modulates the calcium response to antigen stimulation in T lymphocytes. J Immunol. 2009; 183 (10): 6296-6302.
Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Pennington MW et al. Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc Natl Acad Sci U S A. 2006; 103 (46): 17414-17419.
Teisseyre A, Michalak K. Inhibition of the activity of human lymphocyte Kv1.3 potassium channels by res- veratrol. J Membr Biol. 2006; 214 (3): 123-129.
Teisseyre A, Michalak K. Genistein inhibits the activity of kv1.3 potassium channels in human T lymphocytes. J Membr Biol. 2005; 205 (2): 71-79.
Beeton C, Pennington MW, Norton RS. Analogs of the sea anemone potassium channel blocker ShK for the treatment of autoimmune diseases. Inflamm Allergy Drug Targets. 2011; 10 (5): 313-321.
El papel del canal Kv1.3 en el desarrollo de la artritis reumatoide
through extracellular Ca2+ influx and ongoing intracel-
lular Ca2+ mobilization. Biochem J. 1987; 247 (3): 695- 6. Winchester R. Genetic determination of susceptibility 700.
HLA-DRB1 locus, citrullination, and rheumatoid arthritis.
Rashid MH, Huq R, Tanner MR, Chhabra S, Khoo KK, Estrada R et al. A potent and Kv1.3-selective analogue
of the scorpion toxin HsTX1 as a potential therapeutic
for autoimmune diseases. Sci Rep. 2014; 4: 4509.
Gurrola GB, Hernández-López RA, Rodríguez de la
Vega RC, Varga Z, Batista CV, Salas-Castillo SP et al. Structure, function, and chemical synthesis of Vaejovis mexicanus peptide 24: a novel potent blocker of Kv1.3 potassium channels of human T lymphocytes. Biochem- istry. 2012; 51 (19): 4049-4061.
Varga Z, Gurrola-Briones G, Papp F, Rodríguez de la Vega RC, Pedraza-Alva G, Tajhya RB et al. Vm24, a
natural immunosuppressive peptide, potently and se- lectively blocks Kv1.3 potassium channels of human T cells. Mol Pharmacol. 2012; 82 (3): 372-382.
Ahn H, Kim S, Jang HJ, Kim MJ, Rhie DJ, Yoon SH et al. Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone. Naunyn-Schmied Arch Pharmacol. 2007; 374 (4): 305-309.
Bradding P, Wulff H. The K+ channels KCa3.1 and Kv1.3 as novel targets for asthma therapy. Br J Pharmacol. 2009; 157 (8): 1330-1339.
Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic drug targets. Nat Rev Drug Discov. 2009; 8 (12): 982-1001.
Wulff H, Rauer H, Düring T, Hanselmann C, Ruff K, Wrisch A et al. Alkoxypsoralens, novel nonpeptide blockers of Shaker-type K+ channels: synthesis and photoreactivity. J Med Chem. 1998; 41 (23): 4542-4549.
Vennekamp J, Wulff H, Beeton C, Calabresi PA, Griss- mer S, Hansel W et al. Kv1.3-blocking 5-phenylalk- oxypsoralens: a new class of immunomodulators. Mol Pharmacol. 2004; 65 (6): 1364-1374.
Schmitz A, Sankaranarayanan A, Azam P, Schmidt- Lassen K, Homerick D, Hansel W et al. Design of PAP- 1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Mol Pharmacol. 2005; 68 (5): 1254-1270.
Baell JB, Gable RW, Harvey AJ, Toovey N, Herzog T, Hänsel W et al. Khellinone derivatives as blockers of the voltage-gated potassium channel Kv1.3: synthesis
and immunosuppressive activity. J Med Chem. 2004;
(9): 2326-2336.
Harvey AJ, Baell JB, Toovey N, Homerick D, Wulff H.
A new class of blockers of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-position of khellinone. J Med Chem. 2006; 49 (4): 1433-1441.
Miao S, Bao J, Garcia ML, Goulet JL, Hong XJ, Kac- zorowski GJ et al. Benzamide derivatives as blockers of Kv1.3 ion channel. Bioorg Med Chem Lett. 2003; 13 (6): 1161-1164.
Ren YR, Pan F, Parvez S, Fleig A, Chong CR, Xu J et al. Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS One. 2008; 3 (12): e4009.
Beeton C, Wulff H, Singh S, Botsko S, Crossley G, Gut- man GA et al. A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes. J Biol Chem. 2003; 278 (11): 9928-9937.
Mouhat S, Visan V, Ananthakrishnan S, Wulff H, An- dreotti N, Grissmer S et al. K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom. Biochem J. 2005; 385 (Pt 1): 95-104.
Koo GC, Blake JT, Talento A, Nguyen M, Lin S, Sirotina A et al. Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. J Immunol. 1997; 158 (11): 5120-5128.
Hahn SJ, Wang LY, Kaczmarek LK. Inhibition by nystatin of Kv1.3 channels expressed in Chinese hamster ovary cells. Neuropharmacology. 1996; 35 (7): 895-901.
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Copyright (c) 2016 Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra
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