KCNN3 Membrane Protein Introduction

Introduction of KCNN3

Small conductance calcium-activated potassium channel 3 (KCNN3), also known as KCa2.3, is a protein that in humans is encoded by the KCNN3 gene, which is mapped to the chromosome 1q21.3. It is a member of small-conductance potassium channel family, which consists of three members - KCNN1, KCNN2, and KCNN3 sharing 60-70% sequence identity. KCNN3 contains an intracellular N and C termini and six highly conserved transmembrane segments. There are two arrays of polyglutamine (CAG trinucleotide) repeats in the N terminal region.

Basic Information of KCNN3
Protein Name	Small conductance calcium-activated potassium channel protein 3
Gene Name	KCNN3
Aliases	KCa2.3, SK3, SKCa 3, SKCa3
Organism	Homo sapiens (Human)
UniProt ID	Q9UGI6
Transmembrane Times	6
Length (aa)	736
Sequence	MDTSGHFHDSGVGDLDEDPKCPCPSSGDEQQQQQQQQQQQQPPPPAPPAAPQQPLGPSLQPQPPQLQQQQQQQQQQQQQQQQQQQPPHPLSQLAQLQSQPVHPGLLHSSPTAFRAPPSSNSTAILHPSSRQGSQLNLNDHLLGHSPSSTATSGPGGGSRHRQASPLVHRRDSNPFTEIAMSSCKYSGGVMKPLSRLSASRRNLIEAETEGQPLQLFSPSNPPEIVISSREDNHAHQTLLHHPNATHNHQHAGTTASSTTFPKANKRKNQNIGYKLGHRRALFEKRKRLSDYALIFGMFGIVVMVIETELSWGLYSKDSMFSLALKCLISLSTIILLGLIIAYHTREVQLFVIDNGADDWRIAMTYERILYISLEMLVCAIHPIPGEYKFFWTARLAFSYTPSRAEADVDIILSIPMFLRLYLIARVMLLHSKLFTDASSRSIGALNKINFNTRFVMKTLMTICPGTVLLVFSISLWIIAAWTVRVCERYHDQQDVTSNFLGAMWLISITFLSIGYGDMVPHTYCGKGVCLLTGIMGAGCTALVVAVVARKLELTKAEKHVHNFMMDTQLTKRIKNAAANVLRETWLIYKHTKLLKKIDHAKVRKHQRKFLQAIHQLRSVKMEQRKLSDQANTLVDLSKMQNVMYDLITELNDRSEDLEKQIGSLESKLEHLTASFNSLPLLIADTLRQQQQQLLSAIIEARGVSVAVGTTHTPISDSPIGVSSTSFPTPYTSSSSC

Function of KCNN3 Membrane Protein

KCNN3 forms a voltage-independent potassium channel activated by intracellular calcium and is involved in a wide array of physiological processes. KCNN3 is reported to contribute to the development and progression of numerous solid tumors. In melanoma cells, upregulation of KCNN3 enhances cell motility pathways by hyperpolarizing the cell membrane potential. KCNN3 is a mediator of cell migration and cysteine cathepsin-dependent cell invasiveness in breast cancer cells. The expression level of KCNN3 channels in the endothelium influences arterial tone via arterial smooth muscle membrane potential. Mutations in KCNN3 are always related to serious neurological disorders, including schizophrenia, bipolar disorder, Alzheimer's disease, anorexia nervosa, and ataxia as well as myotonic muscular dystrophy.

Fig.1 Schematic model of the proposed endocytosis and recycling of KCa2.3 at the plasma membrane. (Bertuccio, 2018)

Application of KCNN3 Membrane Protein in Literature

Ellinor P.T., et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010, 42(3): 240-4. PubMed ID: 20173747

The article identifies common genetic variants underlying lone AF. The authors identify an association on chromosome 1q21 to lone AF and replicate this association in two independent cohorts with lone AF rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial.
Antonarakis S.E., et al. Lack of linkage or association between schizophrenia and the polymorphic trinucleotide repeat within the KCNN3 gene on chromosome 1q21. Am J Med Genet. 1999, 88(4): 348-51. PubMed ID: 10402501

The results are opposed to the view that larger KCNN3 alleles are preferentially related with schizophrenia in individuals from multiply affected families.
Bonnet-Brilhault F., et al. No evidence for involvement of KCNN3 (hSKCa3) potassium channel gene in familial and isolated cases of schizophrenia. Eur J Hum Genet. 1999, 7(2): 247-50. PubMed ID: 10196711

Their data do not support the involvement of the KCNN3 (hSKCa3) gene in the etiology of schizophrenia as no intergenerational CAG repeat instability was detected.
Grube S., et al. A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. EMBO Mol Med. 2011, 3(6): 309-19. PubMed ID: 21433290

This article suggests that KCNN3 genotypes modify cognitive performance, shown here in a large sample of schizophrenic patients. Reduction of SK3 function may constitute a pharmacological target to improve cognition in schizophrenia and other conditions with cognitive impairment.
Anon B., et al. Possible association of CAG repeat polymorphism in KCNN3 encoding the potassium channel SK3 with oxaliplatin-induced neurotoxicity. Cancer Chemother Pharmacol. 2018, 82(1): 149-157. PubMed ID: 29774408

The authors show a relationship between OIN and CAG repeat polymorphisms of the KCNN3 gene in a preclinical model.

KCNN3 Preparation Options

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Reference

Bertuccio C A, et al. (2018). Plasma membrane insertion of KCa2.3 (SK3) is dependent upon the SNARE proteins, syntaxin-4 and SNAP23. PLoS One. 13(5): e0196717.

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