Na-K-2Cl symporter
Encyclopedia
The Na-K-Cl cotransporter (NKCC, SLC12A2) is a protein
that aids in the active transport
of sodium
, potassium
, and chloride
into and out of cells
. There are two varieties, or isoforms, of this membrane transport protein, called NKCC1 and NKCC2. NKCC1 is widely distributed throughout the body; it has important functions in organs
that secrete
fluids. NKCC2 is found specifically in the kidney
, where it serves to extract sodium, potassium, and chloride from the urine
so that they can be reabsorbed
into the blood
.
(Na), potassium
(K), and chloride
(Cl) ions across the cell membrane
. Because they move each solute in the same direction, NKCC proteins are considered symporter
s. They maintain electroneutrality by moving two positively charged solutes (sodium and potassium) alongside two parts of a negatively charged solute (chloride). Thus the stoichiometry
of the NKCC proteins is 1Na:1K:2Cl.
fluids, called exocrine gland
s. In cells of these organs, NKCC1 is commonly found in the basolateral membrane, the part of the cell membrane
closest to the blood vessel
s. Its basolateral location gives NKCC1 the ability to transport sodium, potassium, and chloride from the blood into the cell. Other transporters assist in the movement of these solutes out of the cell through its apical surface. The end result is that solutes from the blood, particularly chloride, are secreted into the lumen of these exocrine glands, increasing the luminal concentration of solutes and causing water to be secreted as well by osmosis
.
In addition to exocrine glands, NKCC1 is necessary for establishing the potassium-rich endolymph
that bathes part of the cochlea
, an organ necessary for hearing. Inhibition of NKCC1, as with furosemide
or other loop diuretics, can result in deafness.
NKCC1 is also expressed in many regions of the brain
during early development, but not in adulthood. This change in NKCC1 presence seems to be responsible for altering responses to the neurotransmitters GABA
and glycine
from excitatory to inhibitory, which was suggested to be important for early neuronal development. As long as NKCC1 transporters are predominantely active, internal chloride concentrations in neurons is raised in comparison with mature chloride concentrations, which is important for GABA and glycine responses, as respective ligand-gated anion channels are permeable to chloride. With higher internal chloride concentrations, outward driving force for this ions increases, and thus channel opening leads to chloride leaving the cell, thereby depolarizing it. Put another way, increasing internal chloride concentration increases the reversal potential
for chloride, given by the Nernst equation
. Later in development expression of NKCC1 is reduced, while expression of a KCC2 K-Cl cotransporter - increased, thus bringing internal chloride concentration in neurons down to adult values.
s, the basic functional units of the kidney
. Within these cells, NKCC2 resides in the apical membrane abutting the nephron's lumen
, the hollow space containing urine
.
Urine in the thick ascending limb of the loop of Henle has a relatively high concentration of sodium. That is, the electrochemical gradient of sodium favors movement of sodium from the urine and into cells. At this region of the nephron, NKCC2 is the major transport protein by which sodium is reabsorbed from the urine and into cells. According to the stoichiometry outlined above, each molecule of sodium reabsorbed brings one molecule of potassium and two molecules of chloride. Sodium goes on to be reabsorbed into the blood
, where it contributes to the maintenance of blood pressure
.
Furosemide
and other loop diuretic
s inhibit the activity of NKCC2, thereby impairing sodium reabsorption in the thick ascending limb of the loop of Henle. Impaired sodium reabsorption prevents the thick ascending limb from contributing to maintenance of blood pressure. Loop diuretics therefore ultimately result in decreased blood pressure.
s on the long arms
of chromosomes 15 and 5, respectively.
required to move solutes across the cell membrane is provided by the electrochemical gradient
of sodium. Sodium's electrochemical gradient is established by the Na-K ATPase, which is an ATP
-requiring enzyme
. Since NKCC proteins use sodium's gradient, their activity is indirectly dependent on ATP; for this reason, NKCC proteins are said to move solutes by way of secondary active transport
.
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...
that aids in the active transport
Active transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
of 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...
, potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
, 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...
into and out of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. There are two varieties, or isoforms, of this membrane transport protein, called NKCC1 and NKCC2. NKCC1 is widely distributed throughout the body; it has important functions in organs
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
that secrete
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
fluids. NKCC2 is found specifically in the kidney
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...
, where it serves to extract sodium, potassium, and chloride from the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
so that they can be reabsorbed
Reabsorption
In physiology, reabsorption or tubular reabsorption is the flow of glomerular filtrate from the proximal tubule of the nephron into the peritubular capillaries, or from the urine into the blood...
into the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
.
Function
NKCC proteins are membrane transport proteins that transport sodiumSodium
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...
(Na), potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
(K), 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...
(Cl) ions across the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Because they move each solute in the same direction, NKCC proteins are considered symporter
Symporter
A 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....
s. They maintain electroneutrality by moving two positively charged solutes (sodium and potassium) alongside two parts of a negatively charged solute (chloride). Thus the stoichiometry
Stoichiometry
Stoichiometry is a branch of chemistry that deals with the relative quantities of reactants and products in chemical reactions. In a balanced chemical reaction, the relations among quantities of reactants and products typically form a ratio of whole numbers...
of the NKCC proteins is 1Na:1K:2Cl.
NKCC1
NKCC1 is widely distributed throughout the body, especially in organs that secreteSecretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
fluids, called exocrine gland
Exocrine gland
Exocrine glands are a type of ductal glands that secrete their products into ducts that lead directly into the external environment...
s. In cells of these organs, NKCC1 is commonly found in the basolateral membrane, the part of the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
closest to the blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s. Its basolateral location gives NKCC1 the ability to transport sodium, potassium, and chloride from the blood into the cell. Other transporters assist in the movement of these solutes out of the cell through its apical surface. The end result is that solutes from the blood, particularly chloride, are secreted into the lumen of these exocrine glands, increasing the luminal concentration of solutes and causing water to be secreted as well by osmosis
Osmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
.
In addition to exocrine glands, NKCC1 is necessary for establishing the potassium-rich endolymph
Endolymph
Endolymph is the fluid contained in the membranous labyrinth of the inner ear. It is also called Scarpa's fluid, after Antonio Scarpa.-Composition:...
that bathes part of the cochlea
Cochlea
The cochlea is the auditory portion of the inner ear. It is a spiral-shaped cavity in the bony labyrinth, making 2.5 turns around its axis, the modiolus....
, an organ necessary for hearing. Inhibition of NKCC1, as with furosemide
Furosemide
Furosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...
or other loop diuretics, can result in deafness.
NKCC1 is also expressed in many regions of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
during early development, but not in adulthood. This change in NKCC1 presence seems to be responsible for altering responses to the neurotransmitters GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
from excitatory to inhibitory, which was suggested to be important for early neuronal development. As long as NKCC1 transporters are predominantely active, internal chloride concentrations in neurons is raised in comparison with mature chloride concentrations, which is important for GABA and glycine responses, as respective ligand-gated anion channels are permeable to chloride. With higher internal chloride concentrations, outward driving force for this ions increases, and thus channel opening leads to chloride leaving the cell, thereby depolarizing it. Put another way, increasing internal chloride concentration increases the reversal potential
Reversal potential
In a biological membrane, the reversal potential of an ion is the membrane potential at which there is no net flow of that particular ion from one side of the membrane to the other...
for chloride, given by the Nernst equation
Nernst equation
In electrochemistry, the Nernst equation is an equation that can be used to determine the equilibrium reduction potential of a half-cell in an electrochemical cell. It can also be used to determine the total voltage for a full electrochemical cell...
. Later in development expression of NKCC1 is reduced, while expression of a KCC2 K-Cl cotransporter - increased, thus bringing internal chloride concentration in neurons down to adult values.
NKCC2
NKCC2 is specifically found in cells of the thick ascending limb of the loop of Henle in nephronNephron
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....
s, the basic functional units of the kidney
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...
. Within these cells, NKCC2 resides in the apical membrane abutting the nephron's lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
, the hollow space containing urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
.
Urine in the thick ascending limb of the loop of Henle has a relatively high concentration of sodium. That is, the electrochemical gradient of sodium favors movement of sodium from the urine and into cells. At this region of the nephron, NKCC2 is the major transport protein by which sodium is reabsorbed from the urine and into cells. According to the stoichiometry outlined above, each molecule of sodium reabsorbed brings one molecule of potassium and two molecules of chloride. Sodium goes on to be reabsorbed into the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, where it contributes to the maintenance of blood pressure
Blood 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...
.
Furosemide
Furosemide
Furosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...
and other loop diuretic
Loop diuretic
Loop diuretics are diuretics that act on the ascending loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or renal insufficiency...
s inhibit the activity of NKCC2, thereby impairing sodium reabsorption in the thick ascending limb of the loop of Henle. Impaired sodium reabsorption prevents the thick ascending limb from contributing to maintenance of blood pressure. Loop diuretics therefore ultimately result in decreased blood pressure.
Genetics
NKCC1 and NKCC2 are encoded by geneGene
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...
s on the long arms
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
of chromosomes 15 and 5, respectively.
Kinetics
The energyEnergy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
required to move solutes across the cell membrane is provided by the electrochemical gradient
Electrochemical gradient
An electrochemical gradient is a spatial variation of both electrical potential and chemical concentration across a membrane; that is, a combination of the membrane potential and the pH gradient...
of sodium. Sodium's electrochemical gradient is established by the Na-K ATPase, which is an ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
-requiring enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
. Since NKCC proteins use sodium's gradient, their activity is indirectly dependent on ATP; for this reason, NKCC proteins are said to move solutes by way of secondary active transport
Active transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
.