Sodium-chloride symporter
Encyclopedia
The sodium-chloride symporter (also known as Na+-Cl- cotransporter, abbreviated as NCC or NCCT, or as the thiazide-sensitive Na+-Cl- cotransporter or TSC for short) is a cotransporter in the kidney
which has the function of reabsorbing sodium
and chloride
ions from the tubular fluid
into the cells of the distal convoluted tubule
of the nephron
.
It is a member of the SLC12 cotransporter family
of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the gene SLC12A3 (solute carrier family 12 member 3) located in 16q13.
) and CCC9
. The sodium-chloride symporter’s protein sequence has a high degree of identity between different mammalian species
(over 90% between human, rat and mouse).
The ‘‘SLC12A3’’ gene
encodes for a protein
of 1’002 to 1’030 amino acid
residues. NCC is a transmembrane protein
, presumed to have a hydrophobic core of either 10 or 12 transmembrane domains
with intracellular amino- and carboxyl-terminus domains. The exact structure of the NCC protein is unknown, as it has not yet been crystallized
. The NCC protein forms homodimers
at the plasma membrane.
N-glycosylation
occurs in two sites in a long extracellular loop connecting two transmembrane domains within the hydrophobic core. This posttranslational modification
is necessary for proper folding and transport of the protein to the plasma membrane.
and is in contact with the tubular fluid. Using the sodium gradient across the apical membrane of the cells in distal convoluted tubule, the sodium-chloride symporter transports Na+ and Cl- from the tubular fluid into these cells. Afterward, the Na+ is pumped out of the cell and into the bloodstream by the Na+-K+ ATPase located at the basal membrane and the Cl- leaves the cells through the basolateral chloride channel ClC-Kb
. The sodium-chloride symporter accounts for the absorption of 5% of the salt filtered at the glomerulus
.
NCC activity is known to have two control mechanisms affecting protein trafficking to the plasma membrane and transporter kinetics by phosphorylation and de-phosphorylation
of conserved serine/threonine residues.
As NCC has to be at the plasma membrane to function, its activity can be regulated by increasing or decreasing the amount of protein at the plasma membrane. Some NCC modulators, such as the WNK3
and WNK4
kinases may regulate the amount of NCC at the cell surface by inducing the insertion or removal, respectively, of the protein from the plasma membrane.
Furthermore, many residues of NCC can be phosphorylated or dephosphorylated to activate or inhibit NCC uptake of Na+ and Cl-. Other NCC modulators, including intracellular chloride depletion, angiotensin II, aldosterone
and vasopressin
, can regulate NCC activity by phosphorylating conserved serine/threonine residues. NCC activity can be inhibited by thiazide
s, which is why this symporter is also known as the thiazide-sensitive Na+-Cl- cotransporter.
, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria.
Over a hundred different mutations in the NCC gene have been described as causing Gitelman syndrome, including nonsense
, frameshift
, splice site
and missense mutation
s. Two different types of mutations exist within the group of missense mutations causing loss of NCC function. Type I mutations cause a complete loss of NCC function, in which the synthesized protein is not properly glycosylated. NCC protein harboring type I mutations is retained in the endoplasmic reticulum and cannot be trafficked to the cell surface. Type II mutations cause a partial loss of NCC function in which the cotransporter is trafficked to the cell surface but has an impaired insertion in the plasma membrane. NCC harboring type II mutations have normal kinetic properties but are present in lower amounts at the cell surface, resulting in a decreased uptake of sodium and chloride. NCC harboring type II mutations is still under control of its modulators and can still increase or decrease its activity in response to stimuli, whereas type I mutations cause a complete loss of function and regulation of the cotransporter. However, in some patients with Gitelman’s syndrome, no mutations in the NCC gene have been found despite extensive genetic work-up.
in the open population, with both common polymorphisms and rare mutations altering NCC function, renal salt reabsorption and, presumably, blood pressure. Individuals with rare mutations in genes responsible for salt control in the kidney, including NCC, have been found to have a lower blood pressure than controls
. NCC harboring these mutations has a lower function than wild-type cotransporter although some mutations found in individuals in the open population seem to be less deleterious to cotransporter function than mutations in individuals with Gitelman’s syndrome.
Furthermore, heterozygous carriers
of mutations causing Gitelman syndrome (i.e. individuals who have a mutation in one of the two allele
s and do not have the disease) have a lower blood pressure than non-carriers in the same family.
(PHA2), also known as Gordon’s syndrome, is an autosomal dominant disease in which there is an increase in NCC activity leading to short stature, increased blood pressure
, increased serum K+ levels
, increased urinary calcium excretion
and hyperchloremic metabolic acidosis. However, PHA2 is not caused by mutation
s within the NCC gene, but by mutations in NCC regulators WNK1
and WNK4
. Patients respond well to treatment with thiazide-type diuretics.
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
which has the function of reabsorbing sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ions from the tubular fluid
Tubular fluid
Tubular fluid is the fluid in the tubules of the kidney. It starts as a renal ultrafiltrate in the glomerulus, changes composition through the nephron, and ends up as urine leaving through the ureters.-Composition table:...
into the cells of the distal convoluted tubule
Distal convoluted tubule
The distal convoluted tubule is a portion of kidney nephron between the loop of Henle and the collecting duct system.- Physiology :It is partly responsible for the regulation of potassium, sodium, calcium, and pH...
of the nephron
Nephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
.
It is a member of the SLC12 cotransporter family
Solute carrier family
The solute carrier group of membrane transport proteins include over 300 members organized into 51 families. The SLC gene nomenclature system was originally proposed by the Human Genome Organization and is the basis for the official HUGO names of the genes that encode these transporters...
of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the gene SLC12A3 (solute carrier family 12 member 3) located in 16q13.
Molecular biology
The sodium-chloride symporter or NCC is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporter, along with the potassium-chloride cotransporters (K+-Cl- cotransporters or KCCs), the sodium-potassium-chloride cotransporters (Na+-K+-Cl- cotransporters or NKCCs) and orphan member CIP (cotransporter interacting proteinSLC12A9
Solute carrier family 12 member 9 , also known as cation-chloride cotransporter 6 or cation-chloride cotransporter-interacting protein 1 , is a protein that in humans is encoded by the SLC12A9 gene....
) and CCC9
SLC12A8
Solute carrier family 12 member 8 , also known as cation-chloride cotransporter 9 , is a protein that in humans is encoded by the SLC12A8 gene....
. The sodium-chloride symporter’s protein sequence has a high degree of identity between different mammalian species
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
(over 90% between human, rat and mouse).
The ‘‘SLC12A3’’ gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encodes for a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
of 1’002 to 1’030 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. NCC is a transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
, presumed to have a hydrophobic core of either 10 or 12 transmembrane domains
Transmembrane helix
Transmembrane domain usually denotes a single transmembrane alpha helix of a transmembrane protein. It is called a "domain" because an alpha-helix in a membrane can fold independently from the rest of the protein, similar to domains of water-soluble proteins...
with intracellular amino- and carboxyl-terminus domains. The exact structure of the NCC protein is unknown, as it has not yet been crystallized
Protein crystallization
Most Proteins and many biological macromolecules differ from "small" molecules because the environment in which they function is aqueous. Therefore most biological macromolecules can be prompted to form crystals when the solution in which they are dissolved becomes supersaturated. The manner in...
. The NCC protein forms homodimers
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
at the plasma membrane.
N-glycosylation
N-linked glycosylation
N-linked glycosylation is important for the folding of some eukaryotic proteins. The N-linked glycosylation process occurs in eukaryotes and widely in archaea, but very rarely in bacteria....
occurs in two sites in a long extracellular loop connecting two transmembrane domains within the hydrophobic core. This posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
is necessary for proper folding and transport of the protein to the plasma membrane.
Function
Because NCC is located at the apical membrane of the distal convoluted tubule of the nephron, it faces the lumen of the tubuleLumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
and is in contact with the tubular fluid. Using the sodium gradient across the apical membrane of the cells in distal convoluted tubule, the sodium-chloride symporter transports Na+ and Cl- from the tubular fluid into these cells. Afterward, the Na+ is pumped out of the cell and into the bloodstream by the Na+-K+ ATPase located at the basal membrane and the Cl- leaves the cells through the basolateral chloride channel ClC-Kb
CLCNKB
Chloride channel Kb, also known as CLCNKB, is a protein which in humans is encoded by the CLCNKB gene.Chloride channel Kb is a member of the CLC family of voltage-gated chloride channels, which comprises at least 9 mammalian chloride channels. Each is believed to have 12 transmembrane domains and...
. The sodium-chloride symporter accounts for the absorption of 5% of the salt filtered at the glomerulus
Glomerulus
A glomerulus is a capillary tuft that is involved in the first step of filtering blood to form urine.A glomerulus is surrounded by Bowman's capsule, the beginning component of nephrons in the vertebrate kidney. A glomerulus receives its blood supply from an afferent arteriole of the renal...
.
NCC activity is known to have two control mechanisms affecting protein trafficking to the plasma membrane and transporter kinetics by phosphorylation and de-phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of conserved serine/threonine residues.
As NCC has to be at the plasma membrane to function, its activity can be regulated by increasing or decreasing the amount of protein at the plasma membrane. Some NCC modulators, such as the WNK3
WNK3
Serine/threonine-protein kinase WNK3, also known as protein kinase lysine-deficient 3, is a protein that in humans is encoded by the WNK3 gene.- Function :...
and WNK4
WNK4
Serine/threonine-protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene.- Function :The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron...
kinases may regulate the amount of NCC at the cell surface by inducing the insertion or removal, respectively, of the protein from the plasma membrane.
Furthermore, many residues of NCC can be phosphorylated or dephosphorylated to activate or inhibit NCC uptake of Na+ and Cl-. Other NCC modulators, including intracellular chloride depletion, angiotensin II, aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
and vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
, can regulate NCC activity by phosphorylating conserved serine/threonine residues. NCC activity can be inhibited by thiazide
Thiazide
Thiazide is a term used to describe a type of molecule and a class of diuretics often used to treat hypertension and edema ....
s, which is why this symporter is also known as the thiazide-sensitive Na+-Cl- cotransporter.
Gitelman’s syndrome
A loss of NCC function is associated with Gitelman syndromeGitelman syndrome
Gitelman syndrome is a rare inherited defect in the distal convoluted tubule of the kidneys. It causes the kidneys to pass sodium, magnesium, chloride, and potassium into the urine, rather than allowing it to be resorbed into the bloodstream....
, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria.
Over a hundred different mutations in the NCC gene have been described as causing Gitelman syndrome, including nonsense
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
, frameshift
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
, splice site
Splice site mutation
A splice site mutation is a genetic mutation that inserts or deletes a number of nucleotides in the specific site at which splicing of an intron takes place during the processing of precursor messenger RNA into mature messenger RNA. The abolishment of the splicing site results in one or more...
and missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
s. Two different types of mutations exist within the group of missense mutations causing loss of NCC function. Type I mutations cause a complete loss of NCC function, in which the synthesized protein is not properly glycosylated. NCC protein harboring type I mutations is retained in the endoplasmic reticulum and cannot be trafficked to the cell surface. Type II mutations cause a partial loss of NCC function in which the cotransporter is trafficked to the cell surface but has an impaired insertion in the plasma membrane. NCC harboring type II mutations have normal kinetic properties but are present in lower amounts at the cell surface, resulting in a decreased uptake of sodium and chloride. NCC harboring type II mutations is still under control of its modulators and can still increase or decrease its activity in response to stimuli, whereas type I mutations cause a complete loss of function and regulation of the cotransporter. However, in some patients with Gitelman’s syndrome, no mutations in the NCC gene have been found despite extensive genetic work-up.
Hypertension and blood pressure
NCC has also been implicated to play a role in control of blood pressureBlood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
in the open population, with both common polymorphisms and rare mutations altering NCC function, renal salt reabsorption and, presumably, blood pressure. Individuals with rare mutations in genes responsible for salt control in the kidney, including NCC, have been found to have a lower blood pressure than controls
Scientific control
Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...
. NCC harboring these mutations has a lower function than wild-type cotransporter although some mutations found in individuals in the open population seem to be less deleterious to cotransporter function than mutations in individuals with Gitelman’s syndrome.
Furthermore, heterozygous carriers
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
of mutations causing Gitelman syndrome (i.e. individuals who have a mutation in one of the two allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s and do not have the disease) have a lower blood pressure than non-carriers in the same family.
Pseudohypoaldosteronism type II
Type II pseudohypoaldosteronismPseudohypoaldosteronism
Pseudohypoaldosteronism is a condition that mimics hypoaldosteronism. However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback....
(PHA2), also known as Gordon’s syndrome, is an autosomal dominant disease in which there is an increase in NCC activity leading to short stature, increased blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, increased serum K+ levels
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
, increased urinary calcium excretion
Hypercalciuria
Hypercalciuria or hypercalcinuria is the condition of elevated calcium in the urine. Chronic hypercalcinuria may lead to impairment of renal function, nephrocalcinosis, and renal insufficiency....
and hyperchloremic metabolic acidosis. However, PHA2 is not caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s within the NCC gene, but by mutations in NCC regulators WNK1
WNK1
WNK lysine deficient protein kinase 1, also known as WNK1, is an enzyme which in humans is encoded by the WNK1 gene. The human gene is located on short arm of chromosome 12 .WNK1 is also known as Human Accelerated Region 5...
and WNK4
WNK4
Serine/threonine-protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene.- Function :The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron...
. Patients respond well to treatment with thiazide-type diuretics.
See also
- NephronNephronThe renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
- Distal convoluted tubuleDistal convoluted tubuleThe distal convoluted tubule is a portion of kidney nephron between the loop of Henle and the collecting duct system.- Physiology :It is partly responsible for the regulation of potassium, sodium, calcium, and pH...
- ElectrolyteElectrolyteIn chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s, such as sodiumSodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and chlorideChlorideThe chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water... - Cotransporter, including symporterSymporterA cotransporter is an integral membrane protein that is involved in secondary active transport. It works by binding to two molecules or ions at a time and using the gradient of one solute's concentration to force the other molecule or ion against its gradient....
- Blood pressureBlood pressureBlood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
- Diuretics and thiazides