The sodium-chloride symporter (also known as Na
+-Cl
− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na
+-Cl
− cotransporter or TSC) is a
cotransporter Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They e ...
in the
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 ...
which has the function of reabsorbing
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
and
chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
ions
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 conven ...
from the
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
The composition of tubular ...
into the cells of the
distal convoluted tubule
The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.
Physiology
It is partly responsible for the regulation of potassium, sodium, calcium, and pH.
On its apical surface (lumen ...
of the
nephron
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
. It is a member of the
SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the
gene
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 ...
(solute carrier family 12 member 3) located in
16q13.
A loss of NCC function causes
Gitelman syndrome
Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by disease-causing ...
, 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 identified.
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 protein) and
CCC9. The sodium-chloride symporter's
protein sequence
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesi ...
has a high degree of identity between different
mammalian species
''Mammalian Species'' is a peer-reviewed scientific journal published by Oxford University Press on behalf of the American Society of Mammalogists. The journal publishes accounts of 12–35 mammal species yearly. The articles summarize the current ...
(over 90% between human, rat and mouse). The
gene
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 ...
encodes for a
protein
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 ...
of 1,002 to 1,030
amino acid
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 ...
residues. NCC is a
transmembrane protein
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 ...
, presumed to have a
hydrophobic core
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and exclude water molecules. The word hydrophobic literally means "water-fearing", and it describes the segregation of water and nonpolar ...
of either 10 or 12
transmembrane domains
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...
with intracellular
amino- and
carboxyl-terminus domains. The exact structure of the NCC protein is unknown, as it has not yet been
crystallized
Crystallization is the process by which solid forms, where the atoms or molecules are highly organized into a structure known as a crystal. Some ways by which crystals form are precipitating from a solution, freezing, or more rarely depos ...
. The NCC protein forms
homodimers
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
at the plasma membrane.
N-glycosylation
''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...
occurs in two sites in a long extracellular loop connecting two transmembrane domains within the hydrophobic core. This
posttranslational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
is necessary for proper folding and transport of the protein to 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 ...
.
Function
Because NCC is located at the
apical 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 the distal convoluted tubule of the nephron, it faces the
lumen of the tubule 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
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 ...
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
''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn".
''Glomerulus'' may refer to:
* the filter ...
. 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
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
WNK3 is a protein belonging to the 'with no lysine' family of serine-threonine protei ...
and
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. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Go ...
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
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...
,
aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
and
vasopressin
Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...
, can regulate NCC activity by phosphorylating conserved serine/threonine residues.
NCC activity can be inhibited by
thiazide
Thiazide () refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first ...
s, which is why this symporter is also known as the thiazide-sensitive Na
+-Cl
− cotransporter.
Pathology
Gitelman syndrome
A loss of NCC function is associated with
Gitelman syndrome
Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by disease-causing ...
, 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 is a communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous
To be ridiculous is to be something which is ...
,
frameshift
Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
,
splice site
RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' ba ...
and
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
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 pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
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
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
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
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s and do not have the disease) have a lower blood pressure than non-carriers in the same family.
Pseudohypoaldosteronism type II
Type II pseudohypoaldosteronism (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 (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high blo ...
,
increased serum K+ levels,
increased urinary calcium excretion and hyperchloremic metabolic acidosis. However, PHA2 is not caused by
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s within the NCC gene, but by mutations in NCC regulators
WNK1
WNK (lysine deficient protein kinase 1), also known as WNK1, is an enzyme that is encoded by the ''WNK1'' gene. WNK1 is serine-threonine protein kinase and part of the "with no lysine/K" kinase WNK family. The predominant role of WNK1 is the regu ...
and
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. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Go ...
. Patients respond well to treatment with thiazide-type diuretics.
See also
*
Nephron
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
*
Distal convoluted tubule
The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.
Physiology
It is partly responsible for the regulation of potassium, sodium, calcium, and pH.
On its apical surface (lumen ...
*
Electrolyte
An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
s, such as
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
and
chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
*
Cotransporter Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They e ...
, including
symporter
A symporter is an integral membrane protein that is involved in the transport of two (or more) different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the ...
*
Blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
*
Diuretics
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
and
thiazides
Thiazide () refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first ...
References
Further reading
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External links
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{{Membrane transport proteins
Solute carrier family