SLC12A4 Membrane Protein Introduction

Introduction of SLC12A4

Solute carrier family 12 member 4 (also known as KCC1) is a chloride potassium symporter. Most K-Cl cotransport in the erythrocyte is attributed to KCC1. KCC1 activity is volume-, pH-, and chloride-dependent. The regulating mechanisms include cell volume, pH, PO₂, magnesium, calcium, and oxidative changes. Another regulatory pathway of KCC1 activity is a phosphorylation/ dephosphorylation cycle with phosphorylation of the transporter or a regulatory protein decreasing KCC activity and dephosphorylation increasing activity.

Basic Information of SLC12A4
Protein Name	Solute carrier family 12 member 4
Gene Name	SLC12A4/KCC1
Aliases	Electroneutral potassium-chloride cotransporter 1, Erythroid K-Cl cotransporter 1(hKCC1)
Organism	Homo sapiens (Human)
UniProt ID	Q9UP95
Transmembrane Times	12
Length (aa)	1085
Sequence	MPHFTVVPVDGPRRGDYDNLEGLSWVDYGERAELDDSDGHGNHRESSPFLSPLEASRGIDYYDRNLALFEEELDIRPKVSSLLGKLVSYTNLTQGAKEHEEAESGEGTRRRAAEAPSMGTLMGVYLPCLQNIFGVILFLRLTWMVGTAGVLQALLIVLICCCCTLLTAISMSAIATNGVVPAGGSYFMISRSLGPEFGGAVGLCFYLGTTFAAAMYILGAIEILLTYIAPPAAIFYPSGAHDTSNATLNNMRVYGTIFLTFMTLVVFVGVKYVNKFASLFLACVIISILSIYAGGIKSIFDPPVFPVCMLGNRTLSRDQFDICAKTAVVDNETVATQLWSFFCHSPNLTTDSCDPYFMLNNVTEIPGIPGAAAGVLQENLWSAYLEKGDIVEKHGLPSADAPSLKESLPLYVVADIATSFTVLVGIFFPSVTGIMAGSNRSGDLRDAQKSIPVGTILAIITTSLVYFSSVVLFGACIEGVVLRDKYGDGVSRNLVVGTLAWPSPWVIVIGSFFSTCGAGLQSLTGAPRLLQAIAKDNIIPFLRVFGHGKVNGEPTWALLLTALIAELGILIASLDMVAPILSMFFLMCYLFVNLACAVQTLLRTPNWRPRFKYYHWALSFLGMSLCLALMFVSSWYYALVAMLIAGMIYKYIEYQGAEKEWGDGIRGLSLSAARYALLRLEEGPPHTKNWRPQLLVLLKLDEDLHVKYPRLLTFASQLKAGKGLTIVGSVIQGSFLESYGEAQAAEQTIKNMMEIEKVKGFCQVVVASKVREGLAHLIQSCGLGGMRHNSVVLGWPYGWRQSEDPRAWKTFIDTVRCTTAAHLALLVPKNIAFYPSNHERYLEGHIDVWWIVHDGGMLMLLPFLLRQHKVWRKCRMRIFTVAQMDDNSIQMKKDLAVFLYHLRLEAEVEVVEMHNSDISAYTYERTLMMEQRSQMLRQMRLTKTEREREAQLVKDRHSALRLESLYSDEEDESAVGADKIQMTWTRDKYMTETWDPSHAPDNFRELVHIKPDQSNVRRMHTAVKLNEVIVTRSHDARLVLLNMPGPPRNSEGDENYMEFLEVLTEGLERVLLVRGGGREVITIYS

Function of SLC12A4 Membrane Protein

Solute carrier family 12 member 4 (SLC12A4) can mediate electroneutral potassium-chloride cotransport when it is activated by cell swelling. It may help to cell volume homeostasis in single cells and also be involved in the regulation of basolateral Cl- exit in NaCl absorbing epithelia. It is different from other isoforms, SLC12A4 has no transport activity. Moreover, it also influences cation-coupled chloride cotransporters in human.

Fig.1 Two astrocytic subpopulations differing in the gene expression levels of K⁺/Cl⁻ channels. (Jana, 2012)

Application of SLC12A4 Membrane Protein in Literature

Casula S., et al. A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity. J Biol Chem. 2001, 276(45):41870-8. PubMed ID: 11551954

The authors show us the importance of the N- and C-terminal cytoplasmic domains to its K-Cl cotransport function expressed in Xenopus oocytes. They conclude that C-terminal loss-of-function mutants lack a dominant negative phenotype.
Zhang S., et al. The up-regulation of KCC1 gene expression in cervical cancer cells by IGF-II through the ERK1/2MAPK and PI3K/AKT pathways and its significance. Eur J Gynaecol Oncol. 2009, 30(1):29-34. PubMed ID: 19317253

This article shows us that IGF-II can boost KCC1 gene expression in cervical cancer cells through the ERK1/2MAPK and PI3K/AKT signal transduction pathways.
Shmukler B.E., et al. Structure and genetic polymorphism of the mouse KCC1 gene. Biochim Biophys Acta. 2000, 1492(2-3):353-61. PubMed ID: 11004507

In this article, authors find that the intron 1 (AC) repeat in CAST/Ei and SPRET/Ei is not only more divergent in length but also underwent additional sequence variation. An intron 17 B1 Alu-like SINE present in all musculus strains is found to be absent from intron 17 in SPRET/Ei.
Brown F.C., et al. Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model. BLOOD. 2015, 126(26):2863-70. PubMed ID: 26450986

This article finds that a single mutant allele of Kcc1 is able to induce widespread sickling and tissue damage. It provides in vivo evidence that increasing KCC activity worsens end-organ damage and diminishes survival in sickle cell disease.
Casula S., et al. Chemical crosslinking studies with the mouse Kcc1 K-Cl cotransporter. Blood Cells Mol Dis. 2009, 42(3):233-40. PubMed ID: 19380103

The article shows that Kcc1 cross-linking is time-dependent and is independent of protein concentration. Kcc1 cross-linking by the cleavable cross-linker DTME is reversible. They support the oligomeric state of KCC polypeptides.

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Reference

Jana B, et al. (2012). Distinct expression/function of potassium and chloride channels contributes to the diverse volume regulation in cortical astrocytes of GFAP/EGFP mice. PLoS One. 7(1):e29725.

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