KCNN4

Official Full Name

potassium calcium-activated channel subfamily N member 4

Organism

Homo sapiens

Gene ID

3783

Background

The protein encoded by this gene is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. The encoded protein may be part of the predominant calcium-activated potassium channel in T-lymphocytes. This gene is similar to other KCNN family potassium channel genes, but it differs enough to possibly be considered as part of a new subfamily. [provided by RefSeq, Jul 2008]

Synonyms

IK; IK1; SK4; DHS2; KCA4; hIK1; hSK4; IKCA1; hKCa4; KCa3.1; hIKCa1

Bio Chemical Class

Voltage-gated ion channel

Protein Sequence

MGGDLVLGLGALRRRKRLLEQEKSLAGWALVLAGTGIGLMVLHAEMLWFGGCSWALYLFLVKCTISISTFLLLCLIVAFHAKEVQLFMTDNGLRDWRVALTGRQAAQIVLELVVCGLHPAPVRGPPCVQDLGAPLTSPQPWPGFLGQGEALLSLAMLLRLYLVPRAVLLRSGVLLNASYRSIGALNQVRFRHWFVAKLYMNTHPGRLLLGLTLGLWLTTAWVLSVAERQAVNATGHLSDTLWLIPITFLTIGYGDVVPGTMWGKIVCLCTGVMGVCCTALLVAVVARKLEFNKAEKHVHNFMMDIQYTKEMKESAARVLQEAWMFYKHTRRKESHAARRHQRKLLAAINAFRQVRLKHRKLREQVNSMVDISKMHMILYDLQQNLSSSHRALEKQIDTLAGKLDALTELLSTALGPRQLPEPSQQSK

Open

Disease

Alzheimer disease, Chronic pain, Conjunctiva disorder, Neutropenia

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

Cat.No.	Product Name	Price
CSC-RI0112	Human KCNN4 Stable Cell Line-CHO-K1	Inquiry
CSC-DC007998	Panoply™ Human KCNN4 Knockdown Stable Cell Line	Inquiry
CSC-SC007998	Panoply™ Human KCNN4 Over-expressing Stable Cell Line	Inquiry
CSC-RT1379	Human KCNN4 Knockout Cell Line-HeLa	Inquiry
CLKO-1231	KCNN4 KO Cell Lysate-HeLa	Inquiry

Cat.No.	Product Name	Price
AD08455Z	Human KCNN4 adenoviral particles	Inquiry

Cat.No.	Product Name	Price
SHH323623	shRNA set against Human KCNN4 (NM_002250.2)	Inquiry
SHH323627	shRNA set against Mouse KCNN4 (NM_008433.4)	Inquiry

Cat.No.	Product Name	Price
CDCR379234	Rat Kcnn4 ORF Clone(NM_023021.2)	Inquiry
CDFH009687	Human KCNN4 cDNA Clone(NM_002250.2)	Inquiry
CDFH009688	Human KCNN4 cDNA Clone(NM_002250.2)	Inquiry
CDFH009689	Human KCNN4 cDNA Clone(NM_002250.2)	Inquiry
MiUTR1H-05162	KCNN4 miRNA 3'UTR clone	Inquiry
CDCB186747	Rabbit KCNN4 ORF clone (XM_008251273.1)	Inquiry
CDCR239870	Mouse Kcnn4 ORF Clone(NM_001163510.1)	Inquiry
CDCR282796	Human KCNN4 ORF Clone(NM_002250.2)	Inquiry
CDCS410706	Human KCNN4 ORF Clone (BC015337)	Inquiry

Detailed Information

Recent Research

KCNN4, the gene encoding the calcium-activated potassium channel K_Ca3.1, is voltage-independent channels composed of six membrane-spanning domains, modulated by intracellular Ca²⁺ to induce hyperpolarization. In the vascular system, these pathways regulate membrane potential and calcium signaling in addition to their roles in vascular diastole and neointimal formation in cardiovascular disease. Studies have shown that KCNN4 up-regulation is required for mitogen-induced suppression of smooth muscle cell (SMC) markers as well as vascular SMC migration and proliferation, and has been shown to occur during atherosclerosis and restenosis, indicating these channels play an important part in coronary plaque formation.

Up-regulation of KCNN4 has been shown to occur through transcriptional activation of activated protein-1 (AP-1) and reduction of repressor-1 silencing transcription factor (REST). AP-1 is a transcription factor complex composed of c-jun and c-fos dimers involved in the regulation of cell proliferation, growth, and differentiation. Studies have shown that in addition to being activated by growth factors, cytokines, and serum, the AP-1 components are also increased following coronary angioplasty.

In addition, KCNN4 is expressed in intestinal epithelial cells of mice and humans, and plays a central role in the secretion of calcium-activated anions.As the gene has been suggested as a putative modifier of CF severity in humans, silencing KCNN4 greatly improved the survival of CF mice, without alteration of their intestinal secretory function. However, increased levels of mast cell and increased circulating inflammatory cytokines in the intestine of the CF animals were significantly reduced upon Kcnn4 inactivation.

Moreover, KCNN4 is required for osteoclast and macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) formation in rodents and humans. Genetic deletion of KCNN4 reduces macrophage multinucleation through modulation of Ca²⁺ signaling, increases bone mass, and improves clinical outcome in arthritis. Pharmacological blockade of KCNN4 reduces experimental glomerulonephritis. KCNN4 may be a potential therapeutic target for inhibition of bone resorption and chronic inflammation in macrophage multinucleation.

In the end, KCNN4 contributes to the enhanced migratory capacity of alternative-activated microglia. Supporting the pharmacological evidence for roles of KCNN4 in rodent microglia, KCNN4 transcripts are expressed in primary microglia from rats and mice, and KCNN4 protein is present in activated microglia/macrophages in vivo.

References:

Gole H K A, et al. Upregulation of Intermediate-Conductance Ca2+-Activated K+ Channels (KCNN4) in Porcine Coronary Smooth Muscle Requires NADPH Oxidase 5 (NOX5). PLOS ONE, 2014, 9.
Philp A R, et al. Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse. Scientific Reports, 2018, 8(1):9320-.
Schlichter L, et al . IL-4 type 1 receptor signaling up-regulates KCNN4 expression, and increases the KCa3.1 current and its contribution to migration of alternative-activated microglia. Frontiers in Cellular Neuroscience, 2015, 108(2):289a-289a.
Kcnn4 Is a Regulator of Macrophage Multinucleation in Bone Homeostasis and Inflammatory Disease. Cell Reports, 2014, 8(4):1210-1224.
O’Hara Bryan, et al. Multiple Mineralocorticoid Response Elements Localized in Different Introns Regulate Intermediate Conductance K+ (Kcnn4) Channel Expression in the Rat Distal Colon. PLoS ONE, 2014, 9(6):e98695-.

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