Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4)
The protein contains 427 amino acids for an estimated molecular weight of 47696 Da.
Forms a voltage-independent potassium channel that is activated by intracellular calcium (PubMed:26148990). Activation is followed by membrane hyperpolarization which promotes calcium influx. Required for maximal calcium influx and proliferation during the reactivation of naive T-cells (PubMed:17157250, PubMed:18796614). Plays a role in the late stages of EGF-induced macropinocytosis (PubMed:24591580). (updated: Dec. 5, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.
Biological Process
Calcium ion transport
Cell volume homeostasis
Chemical synaptic transmission
Defense response
Immune system process
Ion transport
Phospholipid translocation
Positive regulation of potassium ion transmembrane transport
Positive regulation of protein secretion
Positive regulation of T cell receptor signaling pathway
Potassium ion export
Potassium ion transmembrane transport
Potassium ion transport
Saliva secretion
Stabilization of membrane potential
The reference OMIM entry for this protein is 602754
Potassium channel, calcium-activated, intermediate/small conductance, subfamily n, member 4; kcnn4
Ik1
Sk4
Kca4
Kca3.1
DESCRIPTION
The calcium-activated potassium channels (KCa channels) have been classified into 3 groups. Large conductance (BK) channels are gated by the concerted actions of internal calcium ions and membrane potential and have a unit conductance of 100 to 220 picoSiemens (pS). Intermediate conductance (IK) and small conductance (SK) channels are gated solely by internal calcium ions, with a unit conductance of 20 to 85 pS and 2 to 20 pS, respectively, and are more sensitive to calcium than are BK channels. Each type of channel shows a distinct pharmacology. KCNN4 belongs to a family of IK and SK channels (Ishii et al., 1997).CLONING
Joiner et al. (1997) cloned cDNAs encoding KCNN4, which they called SK4. The predicted 427-amino acid sequence of KCNN4 was approximately 40% identical to that of the rat and human SK channel proteins rSK1, rSK2, rSK3 and hSK1. Sequence analysis revealed that, like the SK channel proteins, KCNN4 contained 6 putative transmembrane domains, a conserved pore region, and a leucine zipper-like motif near the C terminus. By Northern analysis, the authors found that KCNN4 was expressed as 2.6-kb and 3.8-kb transcripts in placenta and at lower levels in lung and pancreas. Joiner et al. (1997) proposed that KCNN4 belongs to a novel subfamily of SK channels. Ishii et al. (1997) also identified a cDNA encoding KCNN4, called IK1 by them. They classified KCNN4 as an IK channel based on its physiologic properties. Independently, Logsdon et al. (1997) isolated a human lymph node cDNA encoding KCNN4, which they called KCa4. Northern analysis revealed that KCNN4 was expressed predominantly as a 2.2-kb mRNA in a variety of tissues, with minor larger transcripts in some tissues. Logsdon et al. (1997) found that the 2.2-kb KCNN4 transcript was 10-fold more abundant in activated T cells than in resting T cells, concomitant with an increase in the KCa channel current.GENE FUNCTION
Joiner et al. (1997) found that KCNN4 generated a conductance of approximately 12 pS and had a very high affinity for calcium when expressed in Chinese hamster ovary cells. They concluded that KCNN4 is a novel SK channel. Ishii et al. (1997) classified KCNN4 as an IK channel because its expression in Xenopus oocytes produced potassium channels with a conductance level of 39 pS that showed the biophysical and pharmacologic properties of native IK channels. Logsdon et al. (1997) found that expression of KCNN4 in mammalian cells produced channels having a conductance of 33 pS, with electrophysiologic properties that were very similar to those reported for the native KCa channel in activated human T lymphocytes. Logsdon et al. (1997) suggested that KCNN4 encodes the predominant KCa channel in T lymphocytes. Hoffman et al. (2003) presented evidence that KCNN4 is the gene that codes for the Ca(2+)-activated K(+) channel (Gardos channel) in red blood cells. This channel is important pathophysiologically, because it represents the major pathway for cell shrinkage via KCl and water loss that occurs in sickle cell disease (603903). Cheong et al. (2005) identified a functional REST (600571)-binding sequence in the promoter region of the KCNN4 gene. REST was expressed in the nuclei of human vascular smooth muscle cells (SMCs), and it downregulated KCNN4 expression in mouse and human vascular SMCs. Downregulated REST and upregulated KCNN4 were evident in SMCs of human neointimal hyperplasia grown in organ culture, and exogenous RE ... More on the omim web site
Dec. 9, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 602754 was added.
Feb. 25, 2016: Protein entry updated
Automatic update: model status changed
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed