In molecular biology, the electroneutral cation-Cl (electroneutral

potassium chloride Potassium chloride (KCl, or potassium salt) is a metal halide salt composed of potassium and chlorine. It is odorless and has a white or colorless vitreous crystal appearance. The solid dissolves readily in water, and its solutions have a salt ...

cotransporter)

family of proteins A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be c ...

are a family of solute carrier

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

. This family includes the products of the Human

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

: SLC12A1, SLC12A1,

SLC12A2 The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two differe ...

, SLC12A3, SLC12A4,

SLC12A5 Potassium-chloride transporter member 5 (aka: KCC2 and SLC12A5) is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentration ...

, SLC12A6, SLC12A7,

SLC12A8 Solute carrier family 12 member 8 (SLC12A8), also known as cation-chloride cotransporter 9 (CCC9), is a protein that in humans is encoded by the SLC12A8 gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to d ...

and

SLC12A9 Solute carrier family 12 member 9 (SLC12A9), also known as cation-chloride cotransporter 6 (CCC6) or cation-chloride cotransporter-interacting protein 1 (CIP1), is a protein that in humans is encoded by the ''SLC12A9'' gene In biology, the w ...

. The K-Cl co-transporter (KCC) mediates the coupled movement of K⁺ and Cl⁻ ions across the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

of many

animal Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...

cells. This transport is involved in the regulatory volume decrease in response to cell swelling in

red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...

, and has been proposed to play a role in the vectorial movement of Cl⁻ across

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

epithelia Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

. The transport process involves one for one electroneutral movement of K⁺ together with Cl⁻, and, in all known

mammalia Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

n cells, the net movement is outward. The neuronal KCC subtype KCC2 is cell-volume insensitive and plays a unique role in maintaining low intracellular Cl⁻concentration, which is required in

neurones A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

for the functioning of Cl⁻ dependent fast synaptic inhibition, mediated by certain neurotransmitters, such as gamma-aminobutyric acid (GABA) and glycine. Three

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

of the K-Cl co-transporter have been described, termed KCC1 (SLC12A4),

KCC2 Potassium-chloride transporter member 5 (aka: KCC2 and SLC12A5) is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentratio ...

(SLC12A5), and KCC3 (SLC12A6), containing 1085, 1116 and 1150

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

, respectively. They are predicted to have 12

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

(TM) regions in a central hydrophobic domain, together with

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...

N- and

C-termini The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

that are likely

cytoplasmic In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...

. Comparison of their

sequence In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...

s with those of other ion-transporting

membrane proteins Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

reveals that they are part of a new superfamily of

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

-chloride co-transporters, which includes the Na-Cl and Na-K-2Cl co-transporters. KCC1 and KCC3 are widely expressed in

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

tissues, while KCC2 is expressed only in

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

neurons, making it likely that this is the

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

responsible for maintaining low Cl⁻

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', an ...

in neurons. A study in the model organism ''C. elegans'' found that the KCC3 ortholog functions in glial cells to regulate animal behavior. KCC1 is widely expressed in

tissues, and when heterologously expressed, possesses the functional characteristics of the well-studied red blood cell K-Cl co-transporter, including stimulation by both swelling and N-ethylmaleimide. Several

splice variant Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...

s have also been identified. KCC3 is widely expressed in human tissues and, like KCC1, is stimulated by both swelling and N-ethylmaleimide. The induction of KCC3 is up-regulated by vascular endothelial growth factor and down-regulated by tumour necrosis factor. Defects in KCC3 are linked to

agenesis In medicine, agenesis () refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue. Many forms of agenesis are referred to by individual names, depending on the organ affected: * A ...

of the corpus callosum with

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...

neuropathy. This disorder is characterised by severe progressive sensorimotor

neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...

, mental retardation,

dysmorphic A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, Genetics, genetic syndrome or birth defect. Dysmorphology is the stud ...

features and complete or partial agenesis of the corpus callosum.

References

{{InterPro content, IPR018491 Protein families