Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or K_v1.3, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''KCNA3''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of c ...

s 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 ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

, 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 A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

proliferation and activation. This gene appears to be intronless and is clustered together with

KCNA2 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. Function Potassium channels represent the most complex class of voltage-gated ion channels from both function ...

and

KCNA10 Potassium voltage-gated channel subfamily A member 10 also known as Kv1.8 is a protein that in humans is encoded by the ''KCNA10'' gene. The protein Proteins are large biomolecules and macromolecules that comprise one or more long chains o ...

genes on chromosome 1.

Function

''KCNA3'' encodes the voltage-gated K_v1.3 channel, which is expressed in T and

B lymphocytes B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

. All human T cells express roughly 300 K_v1.3 channels per cell along with 10-20 calcium-activated K_Ca3.1 channels. Upon activation,

naive Naivety (also spelled naïvety), naiveness, or naïveté is the state of being naive. It refers to an apparent or actual lack of experience and sophistication, often describing a neglect of pragmatism in favor of moral idealism. A ''naïve'' may b ...

and central

memory T cell Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear. Function Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...

s increase expression of the K_Ca3.1 channel to approximately 500 channels per cell, while effector-memory T cells increase expression of the K_v1.3 channel. Among human B cells, naive and early memory B cells express small numbers of K_v1.3 and K_Ca3.1 channels when they are quiescent, and augment K_Ca3.1 expression after activation. In contrast, class-switched memory B cells express high numbers of K_v1.3 channels per cell (about 1500/cell) and this number increases after activation. K_v1.3 is physically coupled through a series of adaptor proteins to the T-cell receptor signaling complex and it traffics to the

immunological synapse In immunology, an immunological synapse (or immune synapse) is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell. The interface was originally named after the neuronal syna ...

during

antigen presentation Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, n ...

. However, blockade of the channel does not prevent immune synapse formation. K_v1.3 and K_Ca3.1 regulate membrane potential and

calcium signaling Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allos ...

of T cells. Calcium entry through the CRAC channel is promoted by potassium efflux through the K_v1.3 and K_Ca3.1 potassium channels. Blockade of K_v1.3 channels in effector-memory T cells suppresses calcium signaling,

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

production (

interferon-gamma Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheeloc ...

, interleukin 2) and cell proliferation. In vivo, K_v1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues. In contrast, K_v1.3 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 K_Ca3.1 channel and are, therefore, protected from the effect of K_v1.3 blockade. K_v1.3 has been reported to be expressed in the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. ...

in lymphocytes. The apoptotic protein Bax has been suggested to insert into the

outer mitochondrial membrane A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

and occlude the pore of K_v1.3 via a lysine residue. Thus, K_v1.3 modulation may be one of many mechanisms that contribute to apoptosis.

Clinical significance

Autoimmune

In patients with multiple sclerosis (MS), disease-associated myelin-specific T cells from the blood are predominantly co-stimulation-independent effector-memory T cells that express high numbers of K_v1.3 channels. T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the K_v1.3 channel. In children with type-1

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, the disease-associated insulin- and GAD65-specific T cells isolated from the blood are effector-memory T cells that express high numbers of K_v1.3 channels, and the same is true of T cells from the synovial joint fluid of patients with

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

. T cells with other antigen specificities in these patients were naive or central memory T cells that upregulate the K_Ca3.1 channel upon activation. Consequently, it should be possible to selectively suppress effector-memory T cells with a K_v1.3-specific blocker and thereby ameliorate many autoimmune diseases without compromising the protective immune response. In proof-of-concept studies, K_v1.3 blockers have prevented and treated disease in rat models of multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, contact dermatitis, and delayed-type hypersensitivity. At therapeutic concentrations, the blockers did not cause any clinically evident toxicity in rodents, and it did not compromise the protective immune response to acute influenza viral infection and acute

chlamydia Chlamydia, or more specifically a chlamydia infection, is a sexually transmitted infection caused by the bacterium '' Chlamydia trachomatis''. Most people who are infected have no symptoms. When symptoms do appear they may occur only several we ...

bacterial infection. Many groups are developing K_v1.3 blockers for the treatment of autoimmune diseases.

Metabolic

K_v1.3 is also considered a therapeutic target for the treatment of obesity, for enhancing peripheral

insulin sensitivity Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood sugar) ...

in patients with type-2 diabetes mellitus, and for preventing

bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...

periodontal disease Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...

. A genetic variation in the K_v1.3 promoter region is associated with low insulin sensitivity and

impaired glucose tolerance Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...

Neurodegeneration

K_v1.3 channels have been found to be highly expressed by activated and plaque-associated microglia in human Alzheimer’s disease (AD) post-mortem brains as well as in mouse models of AD pathology. Patch-clamp recordings and flow cytometric studies performed on acutely isolated mouse microglia have confirmed upregulation of K_v1.3 channels with disease progression in mouse AD models. The K_v1.3 channel gene has also been found to be a regulator of pro-inflammatory microglial responses. Selective blockade of K_v1.3 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.

Blockers

K_v1.3 is blocked by several peptides from venomous creatures including scorpions (ADWX1, OSK1, margatoxin,

kaliotoxin {, style="float: right; clear: right; margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" align="right" width="280" !The amino acid sequence of Kaliotoxin , - , bgcolor="#eeeeee" , N - Gly - Val - Glu - Ile ...

, charybdotoxin,

noxiustoxin Noxiustoxin (NTX) is a toxin from the venom of the Mexican scorpion ''Centruroides'' noxius Hoffmann which block voltage-dependent potassium channels and calcium-activated potassium channels. Sources NTX was first purified from homogenized c ...

, anuroctoxin, OdK2) and sea anemone ( ShK, ShK-F6CA, ShK-186, ShK-192, BgK), and by

small molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...

compounds (e.g., PAP-1, Psora-4, correolide, benzamides, CP339818, progesterone and the anti-lepromatous drug

clofazimine 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 sup ...

). The K_v1.3 blocker clofazimine has been reported to be effective in the treatment of chronic graft-versus-host disease, cutaneous lupus, and pustular psoriasis 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

immunomodulator Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

y effect by clofazimine.

References

External links

* * {{NLM content Ion channels