KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4): A Key Regulator of Calcium-Activated Potassium Currents
Explore the KCNN4 gene, its protein product (KCa3.1), associated diseases, expression patterns, mutations, and functional roles in cellular physiology.
Gene Information Card
| Symbol | KCNN4 |
|---|---|
| Full Name | Potassium Calcium-Activated Channel Subfamily N Member 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 19q13.31 (GRCh38) |
| NCBI Gene ID | 3783 ncbi.nlm.nih.gov/gene/3783 |
| Ensembl ID | ENSG00000104783 |
| UniProt ID | Q15554 |
| OMIM ID | 602754 |
| HGNC ID | 6293 |
| Aliases | KCa3.1, IK1, SK4, hKCa4, KCNN4a, KCNN4b |
Description
The KCNN4 gene encodes a member of the calcium-activated potassium channel family, specifically the intermediate-conductance calcium-activated potassium channel KCa3.1 (also known as IK1 or SK4). This channel is activated by intracellular calcium and plays a critical role in regulating membrane potential and calcium signaling in various cell types, including immune cells, erythrocytes, and epithelial cells. KCNN4 is involved in processes such as T-cell activation, cell volume regulation, and vascular tone. Mutations in KCNN4 have been linked to hereditary xerocytosis and other disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hereditary Xerocytosis (HX) | Gain-of-function mutations in KCNN4 lead to increased potassium efflux, causing dehydration of red blood cells and hemolytic anemia. | ClinVar, OMIM |
| Dehydrated Hereditary Stomatocytosis (DHS) | Same mechanism as HX; KCNN4 mutations cause altered red cell cation permeability, leading to stomatocytosis. | ClinVar, OMIM |
| Sickle Cell Disease (modifier) | KCNN4 activity contributes to red blood cell dehydration, exacerbating sickling; inhibition of KCNN4 is a therapeutic target. | PubMed, COSMIC |
| Immunodeficiency (rare) | Loss-of-function mutations may impair T-cell calcium signaling and proliferation, though clinical evidence is limited. | UniProt, OMIM |
| Cancer (potential) | KCNN4 overexpression in various cancers promotes cell proliferation, migration, and invasion; not a direct germline disease but a somatic alteration. | COSMIC, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Blood | High | High |
| Spleen | Medium | Medium |
| Bone Marrow | Medium | Medium |
| Lung | Low | Low |
| Kidney | Low | Low |
| Gastrointestinal Tract | Low | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Erythrocytes | High | Key channel for red cell volume regulation |
| T lymphocytes | High | Critical for calcium signaling and activation |
| Endothelial cells | Medium | Regulates vascular tone |
| Epithelial cells (colon, lung) | Medium | Involved in ion transport |
| Cancer cell lines (e.g., HeLa, MCF7) | Variable | Overexpressed in some cancers |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Arg352His | Missense | Rare (found in HX families) | Gain-of-function: increased calcium sensitivity |
| p.Val282Met | Missense | Rare (HX) | Gain-of-function: altered gating |
| p.Arg236His | Missense | Rare (HX) | Gain-of-function |
| p.Gly352Ser | Missense | Rare (HX) | Gain-of-function |
| p.Leu105Pro | Missense | Rare (HX) | Gain-of-function |
| Somatic mutations in cancer | Various | Low frequency in tumors | May alter channel activity, promoting tumor progression |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations are rare and may lead to impaired immune function due to defective T-cell calcium signaling, but clinical phenotypes are not well-defined.
Gain of Function (GOF)
Most reported pathogenic mutations are gain-of-function, leading to increased potassium efflux and red blood cell dehydration, causing hereditary xerocytosis.
Dominant Negative (DN)
No dominant-negative mutations have been reported for KCNN4.
View complete mutation data：
Gene Ontology (GO)
| • calcium-activated potassium channel activity | • potassium ion transmembrane transport |
| • plasma membrane | • response to calcium ion |
| • regulation of membrane potential | • cell volume homeostasis |
| • T cell activation |
Pathways
• Calcium signaling pathway
• T cell receptor signaling pathway
• Ion transport
• Regulation of actin cytoskeleton
Protein Summary
The KCNN4 protein, also known as KCa3.1, is a 427-amino acid integral membrane protein with six transmembrane domains and a cytoplasmic C-terminus. It forms a homotetrameric channel that is activated by intracellular calcium via calmodulin binding. The channel is selective for potassium ions and mediates intermediate-conductance calcium-activated potassium currents. It plays a crucial role in maintaining membrane potential, regulating calcium influx, and controlling cell volume. Structurally, it contains a conserved pore-forming region and a calmodulin-binding domain. The protein is expressed in various tissues, with highest levels in blood cells, and is a target for therapeutic intervention in sickle cell disease and immune disorders.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| KCNN4 Knockout HEK293 Cell Line | EDJ-KQ5049 | Human | 3783 | Details Get a Quote |
| KCNN4 Knockout A-549 Cell Line | EDJ-KQ27950 | Human | 3783 | Details Get a Quote |
| KCNN4 Knockout HeLa Cell Line | EDJ-KQ27952 | Human | 3783 | Details Get a Quote |
| KCNN4 Knockout HCT 116 Cell Line | EDJ-KQ26737 | Human | 3783 | Details Get a Quote |
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