KCNA3

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KCNA3
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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 MbChr 3: 106.94 – 106.95 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

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

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,

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

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

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,

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,

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

immunomodulatory effect by clofazimine.[65]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000177272 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047959 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: KCNA3 potassium voltage-gated channel, shaker-related subfamily, member 3".
  6. ^
    PMID 2251283
    .
  7. S2CID 219195192
    .
  8. S2CID 4340921
    .
  9. S2CID 30410512
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  10. PMID 6088661
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  11. PMID 2305265
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  12. S2CID 45657700
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  13. PMID 1547020
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  14. ^
    PMID 15120495
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  15. ^
    PMID 12782673
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  16. ^
    PMID 15240664
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  17. PMID 14745040
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  18. ^
    PMID 17088564
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  19. ^
    PMID 18835197
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  20. ^
    PMID 15632141
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  21. ^
    PMID 18818304
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  22. PMID 8702786
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  23. PMID 12807917
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  24. PMID 18940791
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  25. PMID 11602626
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  26. PMID 16043714
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  27. ^
    PMID 11717451
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  28. PMID 15665253
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  29. PMID 17984097
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  30. PMID 17273162
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  31. PMID 14579513
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  32. PMID 18542083
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  33. PMID 12588802
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  34. PMID 14981264
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  35. ^
    S2CID 37002854
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  36. PMID 16317062
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  37. PMID 25362031
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  38. ^
    PMID 29272333
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  39. ^
    PMID 29784049
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  40. PMID 28651603
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  41. S2CID 8598481
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  42. S2CID 21383597
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  43. PMID 18471844
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  44. S2CID 18538305
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  45. S2CID 12308227
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  46. PMID 8645244
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  47. S2CID 9180663
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  48. PMID 9830012
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  49. PMID 10419508
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  50. PMID 18480054
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  51. PMID 19122005
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  52. PMID 9063464
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  53. S2CID 6931552
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  54. PMID 25976092
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  55. PMID 10607427
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  56. PMID 12643934
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  57. PMID 8967992
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  58. PMID 9802971
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  59. PMID 19104661
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  60. PMID 9116272
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  61. PMID 16200586
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  62. S2CID 43528153
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  63. S2CID 36255192
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  64. PMID 7829710
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  65. PMID 17570206
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External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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