Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the KCNA3gene.[5][6][7]
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes – shaker, shaw, shab, and shal – have been identified in Drosophila, and each has been shown to have human homolog(s).
This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. It plays an essential role in T cell proliferation and activation. This gene appears to be intronless and is clustered together with KCNA2 and KCNA10 genes on chromosome 1.[5]
Function
KCNA3 encodes the voltage-gated Kv1.3 channel, which is expressed in T and B lymphocytes.[6][8][9][10][11][12][13] All human T cells express roughly 300 Kv1.3 channels per cell along with 10-20 calcium-activated KCa3.1 channels.[14][15] Upon activation, naive and central memory T cells increase expression of the KCa3.1 channel to approximately 500 channels per cell, while effector-memory T cells increase expression of the Kv1.3 channel.[14][15] Among human B cells, naive and early memory B cells express small numbers of Kv1.3 and KCa3.1 channels when they are quiescent, and augment KCa3.1 expression after activation.[16] In contrast, class-switched memory B cells express high numbers of Kv1.3 channels per cell (about 1500/cell) and this number increases after activation.[16]
Kv1.3 is physically coupled through a series of adaptor proteins to the T-cell receptor signaling complex and it traffics to the immunological synapse during antigen presentation.[17][18] However, blockade of the channel does not prevent immune synapse formation.[18] Kv1.3 and KCa3.1 regulate membrane potential and calcium signaling of T cells.[14] Calcium entry through the CRAC channel is promoted by potassium efflux through the Kv1.3 and KCa3.1 potassium channels.[18][19]
Blockade of Kv1.3 channels in effector-memory T cells suppresses calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.[14][15][18] In vivo, Kv1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues.[19] In contrast, Kv1.3 blockers do not affect the homing to and motility within lymph nodes of naive and central memory T cells, most likely because these cells express the KCa3.1 channel and are, therefore, protected from the effect of Kv1.3 blockade.[19]
In patients with multiple sclerosis (MS), disease-associated myelin-specific T cells from the blood are predominantly co-stimulation-independent[25] effector-memory T cells that express high numbers of Kv1.3 channels.[15][18] T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the Kv1.3 channel.[26] In children with type-1 diabetes mellitus, the disease-associated insulin- and GAD65-specific T cells isolated from the blood are effector-memory T cells that express high numbers of Kv1.3 channels, and the same is true of T cells from the synovial joint fluid of patients with rheumatoid arthritis.[18] T cells with other antigen specificities in these patients were naive or central memory T cells that upregulate the KCa3.1 channel upon activation.[18] Consequently, it should be possible to selectively suppress effector-memory T cells with a Kv1.3-specific blocker and thereby ameliorate many autoimmune diseases without compromising the protective immune response. In proof-of-concept studies, Kv1.3 blockers have prevented and treated disease in rat models of multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, contact dermatitis, and delayed-type hypersensitivity.[18][27][28][29][30]
At therapeutic concentrations, the blockers did not cause any clinically evident toxicity in rodents,[18][27] and it did not compromise the protective immune response to acute influenza viral infection and acute chlamydia bacterial infection.[19] Many groups are developing Kv1.3 blockers for the treatment of autoimmune diseases.[31]
Kv1.3 channels have been found to be highly expressed by activated and plaque-associated microglia in human Alzheimer's disease (AD) post-mortem brains [37] as well as in mouse models of AD pathology.[38] Patch-clamp recordings and flow cytometric studies performed on acutely isolated mouse microglia have confirmed upregulation of Kv1.3 channels with disease progression in mouse AD models.[38][39] The Kv1.3 channel gene has also been found to be a regulator of pro-inflammatory microglial responses.[40] Selective blockade of Kv1.3 channels by the small molecule Pap1 as well as a peptide sea anemone toxin-based peptide ShK-223 have been found to limit amyloid beta plaque burden in mouse AD models, potentially via augmented clearance by microglia.[38][39]
^Chandy KG, Williams CB, Spencer RH, Aguilar BA, Ghanshani S, Tempel BL, Gutman GA (February 1990). "A family of three mouse potassium channel genes with intronless coding regions". Science. 247 (4945): 973–5. Bibcode:1990Sci...247..973C. doi:10.1126/science.2305265. PMID2305265.
^Cai YC, Osborne PB, North RA, Dooley DC, Douglass J (March 1992). "Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel". DNA and Cell Biology. 11 (2): 163–72. doi:10.1089/dna.1992.11.163. PMID1547020.
^Wulff H, Beeton C, Chandy KG (September 2003). "Potassium channels as therapeutic targets for autoimmune disorders". Current Opinion in Drug Discovery & Development. 6 (5): 640–7. PMID14579513.
^Bagdány M, Batista CV, Valdez-Cruz NA, Somodi S, Rodriguez de la Vega RC, Licea AF, Varga Z, Gáspár R, Possani LD, Panyi G (April 2005). "Anuroctoxin, a new scorpion toxin of the alpha-KTx 6 subfamily, is highly selective for Kv1.3 over IKCa1 ion channels of human T lymphocytes". Molecular Pharmacology. 67 (4): 1034–44. doi:10.1124/mol.104.007187. PMID15615696. S2CID12308227.
^Pennington MW, Mahnir VM, Krafte DS, Zaydenberg I, Byrnes ME, Khaytin I, Crowley K, Kem WR (February 1996). "Identification of three separate binding sites on SHK toxin, a potent inhibitor of voltage-dependent potassium channels in human T-lymphocytes and rat brain". Biochemical and Biophysical Research Communications. 219 (3): 696–701. doi:10.1006/bbrc.1996.0297. PMID8645244.
^Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick D, Hänsel W, Wulff H (November 2005). "Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases". Molecular Pharmacology. 68 (5): 1254–70. doi:10.1124/mol.105.015669. PMID16099841. S2CID6931552.
^Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EI (October 2005). "Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus". Arthritis and Rheumatism. 52 (10): 3073–8. doi:10.1002/art.21358. PMID16200586.
^Arbiser JL, Moschella SL (February 1995). "Clofazimine: a review of its medical uses and mechanisms of action". Journal of the American Academy of Dermatology. 32 (2 Pt 1): 241–7. doi:10.1016/0190-9622(95)90134-5. PMID7829710.
^Selby W, Pavli P, Crotty B, Florin T, Radford-Smith G, Gibson P, Mitchell B, Connell W, Read R, Merrett M, Ee H, Hetzel D (June 2007). "Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease". Gastroenterology. 132 (7): 2313–9. doi:10.1053/j.gastro.2007.03.031. PMID17570206.
