KCNA3

Last updated
KCNA3
Protein KCNA3 PDB 1dsx.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KCNA3 , HGK5, HLK3, HPCN3, HUKIII, KV1.3, MK3, PCN3, potassium voltage-gated channel subfamily A member 3
External IDs OMIM: 176263; MGI: 96660; HomoloGene: 128570; GeneCards: KCNA3; OMA:KCNA3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3738

16491

Ensembl

ENSG00000177272

ENSMUSG00000047959

UniProt

P22001

P16390

RefSeq (mRNA)

NM_002232

NM_008418

RefSeq (protein)

NP_002223

NP_032444

Location (UCSC) Chr 1: 110.67 – 110.67 Mb Chr 3: 106.94 – 106.95 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 KCNA3 gene. [5] [6] [7]

Contents

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]

Kv1.3 has been reported to be expressed in the inner mitochondrial membrane in lymphocytes. [20] The apoptotic protein Bax has been suggested to insert into the outer mitochondrial membrane and occlude the pore of Kv1.3 via a lysine residue. [21] Thus, Kv1.3 modulation may be one of many mechanisms that contribute to apoptosis. [20] [21] [22] [23] [24]

Clinical significance

Autoimmune

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]

Metabolic

Kv1.3 is also considered a therapeutic target for the treatment of obesity, [32] [33] for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus, [34] and for preventing bone resorption in periodontal disease. [35] A genetic variation in the Kv1.3 promoter region is associated with low insulin sensitivity and impaired glucose tolerance. [36]

Neurodegeneration

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]

Blockers

Kv1.3 is blocked [35] by several peptides from venomous creatures including scorpions (ADWX1, OSK1, [41] margatoxin, [42] kaliotoxin, charybdotoxin, noxiustoxin, anuroctoxin, OdK2 [43] ) [44] [45] and sea anemone (ShK, [46] [47] [48] [49] [50] ShK-F6CA, ShK-186, ShK-192, [51] BgK [52] ), and by small molecule compounds (e.g., PAP-1, [53] Psora-4, [54] correolide, [55] benzamides, [56] CP339818, [57] progesterone [58] and the anti-lepromatous drug clofazimine [59] ). The Kv1.3 blocker clofazimine has been reported to be effective in the treatment of chronic graft-versus-host disease, [60] cutaneous lupus, [61] [62] and pustular psoriasis [63] [64] in humans. Furthermore, clofazimine in combination with the antibiotics clarithromycin and rifabutin induced remission for about 2 years in patients with Crohn's disease, but the effect was temporary; the effect was thought to be due to anti-mycobacterial activity, but could well have been an immunomodulatory effect by clofazimine. [65]

See also

Related Research Articles

<span class="mw-page-title-main">Clofazimine</span> Medication

Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to support its use in other conditions though a retrospective study found it 95% effective in the treatment of Mycobacterium avium complex (MAC) when administered with a macrolide and ethambutol, as well as the drugs amikacin and clarithromycin. However, in the United States, clofazimine is considered an orphan drug, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the Food and Drug Administration. It is taken orally.

<span class="mw-page-title-main">Kv1.1</span>

Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene. Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.

<span class="mw-page-title-main">Voltage-gated potassium channel</span> Class of transport proteins

Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

<span class="mw-page-title-main">Margatoxin</span>

Margatoxin (MgTX) is a peptide that selectively inhibits Kv1.3 voltage-dependent potassium channels. It is found in the venom of Centruroides margaritatus, also known as the Central American Bark Scorpion. Margatoxin was first discovered in 1993. It was purified from scorpion venom and its amino acid sequence was determined.

<span class="mw-page-title-main">KCNA5</span> Protein-coding gene in humans

Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.

<span class="mw-page-title-main">KCNA2</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.

<span class="mw-page-title-main">KCNA4</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">KCNN4</span> Protein-coding gene in the species Homo sapiens

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4, also known as KCNN4, is a human gene encoding the KCa3.1 protein.

<span class="mw-page-title-main">KCNAB1</span> Protein-coding gene in the species Homo sapiens

Voltage-gated potassium channel subunit beta-1 is a protein that in humans is encoded by the KCNAB1 gene.

<span class="mw-page-title-main">KCNA7</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily A member 7 also known as Kv1.7 is a protein that in humans is encoded by the KCNA7 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit. It may contribute to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">Stichodactyla toxin</span> Protein family

Stichodactyla toxin is a 35-residue basic peptide from the sea anemone Stichodactyla helianthus that blocks a number of potassium channels. Related peptides form a conserved family of protein domains known as the ShkT domain. Another well-studied toxin of the family is BgK from Bunodosoma granulifera.

Kaliotoxin (KTX) inhibits potassium flux through the Kv1.3 voltage-gated potassium channel and calcium-activated potassium channels by physically blocking the channel-entrance and inducing a conformational change in the K+-selectivity filter of the channel.

Mast cell degranulating (MCD) peptide is a cationic 22-amino acid residue peptide, which is a component of the venom of the bumblebee. At low concentrations, MCD peptide can stimulate mast cell degranulation. At higher concentrations, it has anti-inflammatory properties. In addition, it is a potent blocker of voltage-sensitive potassium channels.

<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

Pi3 toxin is a purified peptide derivative of the Pandinus imperator scorpion venom. It is a potent blocker of voltage-gated potassium channel, Kv1.3 and is closely related to another peptide found in the venom, Pi2.

Gambierol is a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Gambierol is collected from the sea at the Rangiroa Peninsula in French Polynesia. The toxins are accumulated in fish through the food chain and can therefore cause human intoxication. The symptoms of the toxicity resemble those of ciguatoxins, which are extremely potent neurotoxins that bind to voltage-sensitive sodium channels and alter their function. These ciguatoxins cause ciguatera fish poisoning. Because of the resemblance, there is a possibility that gambierol is also responsible for ciguatera fish poisoning. Because the natural source of gambierol is limited, biological studies are hampered. Therefore, chemical synthesis is required.

<span class="mw-page-title-main">ImKTx88</span>

ImKTx88 is a selective inhibitor of the Kv1 ion channel family that can be isolated from the venom of the Isometrus maculatus. This peptide belongs to the α-KTx subfamily and is classified as a pore-blocking toxin.

MeuKTX, which belongs to the α-KTx toxin subfamily, is a neurotoxin present in the venom of Mesobuthus eupeus. This short-chain peptide blocks potassium channels, such as Kv1.1, Kv1.2 and Kv1.3.

Christine Beeton is an immunologist and associate professor at the Baylor College of Medicine in Houston, Texas. She works within the Department of Molecular Physiology and Biophysics. Beeton graduated from the Faculté des Sciences de Luminy within the Université de la Mediterranée in Marseille, France and later as a postdoctoral fellow from the University of California. Her professional interests and areas of expertise include autoimmune diseases, drug development, ions and ion channels in disease, and targeted therapies.

<span class="mw-page-title-main">OdK2</span>

OdK2 is a toxin found in the venom of the Iranian scorpion Odonthobuthus doriae. It belongs to the α-KTx family, and selectively blocks the voltage-gated potassium channel Kv1.3 (KCNA3).

Toxin BF9 is a Kunitz-type peptide, coming from snakes, with a dual functionality. The toxin is able to inhibit both serine proteases and potassium channels.

References

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  36. ↑ Tschritter O, Machicao F, Stefan N, Schäfer S, Weigert C, Staiger H, Spieth C, Häring HU, Fritsche A (February 2006). "A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance". The Journal of Clinical Endocrinology and Metabolism. 91 (2): 654–8. doi: 10.1210/jc.2005-0725 . PMID   16317062.
  37. ↑ Rangaraju S, Gearing M, Jin LW, Levey A (2015-02-06). "Potassium channel Kv1.3 is highly expressed by microglia in human Alzheimer's disease". Journal of Alzheimer's Disease. 44 (3): 797–808. doi:10.3233/jad-141704. PMC   4402159 . PMID   25362031.
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  39. 1 2 Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, Duong DM, Pennington MW, Lah JJ, Seyfried NT, Levey AI (May 2018). "Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease". Molecular Neurodegeneration. 13 (1): 24. doi: 10.1186/s13024-018-0254-8 . PMC   5963076 . PMID   29784049.
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