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Na–K–Cl cotransporter
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Na–K–Cl cotransporter
The Na–K–Cl cotransporter (NKCC) is a transport 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 different genes (SLC12A2 and SLC12A1 respectively). Two isoforms of the NKCC1/Slc12a2 gene result from keeping (isoform 1) or skipping (isoform 2) exon 21 in the final gene product.
NKCC1 is widely distributed throughout the human body; it has important functions in organs that secrete fluids. In contrast, NKCC2 is found specifically in the kidney, where it extracts sodium, potassium, and chloride from the urine so they can be reabsorbed into the blood.
NKCC proteins are membrane transport proteins that transport sodium (Na), potassium (K), and chloride (Cl) ions across the cell membrane. Because they move each solute in the same direction, they are considered symporters. 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 transported solutes is 1Na:1K:2Cl. Although squid giant axons are the only notable exception with a stoichiometry of 2Na:1K:3Cl, electroneutrality across the protein transporter is still maintained. The rate of transport of these ions are regulated by phosphorylation sites, which present on both NKCC isoforms.
The NKCC1 isoform consists of about 1,200 amino acids, with about 500 amino acids residues giving rise to twelve hydrophobic transmembrane regions. However, evidence of a shorter NKCC1 mRNA transcript (6.7 kb to 7-7.5 kb) in skeletal muscle cells gives support that further NKCC1 variants exists in a tissue-specific manner. The carboxy-terminal of the NKCC1 cotransporter contains multiple phosphorylation sites and is highly conserved across species, while in contrast, the amino-terminal contains at least one phosphorylation site and is poorly conserved across species.Focusing on the transmembrane regions, mutagenesis-driven affinity studies have revealed the second transmembrane region as the determinant of cation affinity, while chloride affinity was determined by transmembrane regions four through seven. Additionally, bumetanide, a loop diuretic, was found to bind to transmembrane regions 2 through 7, 11, and 12.
NKCC1 is widely distributed throughout the body, especially in organs that secrete fluids, called exocrine glands. In cells of these organs, NKCC1 is commonly found in the basolateral membrane, the part of the cell membrane closest to the blood vessels. Exon 21 possesses a translocation sequence that targets NKCC1 to the basolateral membrane. Thus, NKCC1 cotransporters that have been alternatively spliced to exclude exon 21 will be translocated to the apical membrane rather than the basolateral membrane. 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 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. Specifically in the cochlea, NKCC1 is present in the stria vascularis, spiral ligament, and spiral ganglia. Similarly, NKCC1 expression decreases with aging, resulting in progressive hearing loss. Additionally, NKCC1 is present in the dark cells of the vestibule and contributes to generation of the endolymph of the vestibular system.
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 predominantly 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.
NKCC1 has been identified in Sertoli cells, spermatocytes, and spermatids in the male reproductive system. NKCC1 function appears to be critical for spermatogenesis, as knockdown of NKCC1 in mice results in spermatocytes failing to mature into spermatozoa, resulting in infertility. Additionally, the NKCC1 knockdown mice also exhibit a decreased testicle size compared to wild-type mice. The mechanism behind NKCC1-dependent male fertility is unclear, it is possible that the observed decreased sperm count could be due to either lack of NKCC1 cotransport in the testis or upstream failure of NKCC1-expressing neurons in the hypothalamus to release gonadotropin-releasing hormone.
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Na–K–Cl cotransporter
The Na–K–Cl cotransporter (NKCC) is a transport 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 different genes (SLC12A2 and SLC12A1 respectively). Two isoforms of the NKCC1/Slc12a2 gene result from keeping (isoform 1) or skipping (isoform 2) exon 21 in the final gene product.
NKCC1 is widely distributed throughout the human body; it has important functions in organs that secrete fluids. In contrast, NKCC2 is found specifically in the kidney, where it extracts sodium, potassium, and chloride from the urine so they can be reabsorbed into the blood.
NKCC proteins are membrane transport proteins that transport sodium (Na), potassium (K), and chloride (Cl) ions across the cell membrane. Because they move each solute in the same direction, they are considered symporters. 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 transported solutes is 1Na:1K:2Cl. Although squid giant axons are the only notable exception with a stoichiometry of 2Na:1K:3Cl, electroneutrality across the protein transporter is still maintained. The rate of transport of these ions are regulated by phosphorylation sites, which present on both NKCC isoforms.
The NKCC1 isoform consists of about 1,200 amino acids, with about 500 amino acids residues giving rise to twelve hydrophobic transmembrane regions. However, evidence of a shorter NKCC1 mRNA transcript (6.7 kb to 7-7.5 kb) in skeletal muscle cells gives support that further NKCC1 variants exists in a tissue-specific manner. The carboxy-terminal of the NKCC1 cotransporter contains multiple phosphorylation sites and is highly conserved across species, while in contrast, the amino-terminal contains at least one phosphorylation site and is poorly conserved across species.Focusing on the transmembrane regions, mutagenesis-driven affinity studies have revealed the second transmembrane region as the determinant of cation affinity, while chloride affinity was determined by transmembrane regions four through seven. Additionally, bumetanide, a loop diuretic, was found to bind to transmembrane regions 2 through 7, 11, and 12.
NKCC1 is widely distributed throughout the body, especially in organs that secrete fluids, called exocrine glands. In cells of these organs, NKCC1 is commonly found in the basolateral membrane, the part of the cell membrane closest to the blood vessels. Exon 21 possesses a translocation sequence that targets NKCC1 to the basolateral membrane. Thus, NKCC1 cotransporters that have been alternatively spliced to exclude exon 21 will be translocated to the apical membrane rather than the basolateral membrane. 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 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. Specifically in the cochlea, NKCC1 is present in the stria vascularis, spiral ligament, and spiral ganglia. Similarly, NKCC1 expression decreases with aging, resulting in progressive hearing loss. Additionally, NKCC1 is present in the dark cells of the vestibule and contributes to generation of the endolymph of the vestibular system.
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 predominantly 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.
NKCC1 has been identified in Sertoli cells, spermatocytes, and spermatids in the male reproductive system. NKCC1 function appears to be critical for spermatogenesis, as knockdown of NKCC1 in mice results in spermatocytes failing to mature into spermatozoa, resulting in infertility. Additionally, the NKCC1 knockdown mice also exhibit a decreased testicle size compared to wild-type mice. The mechanism behind NKCC1-dependent male fertility is unclear, it is possible that the observed decreased sperm count could be due to either lack of NKCC1 cotransport in the testis or upstream failure of NKCC1-expressing neurons in the hypothalamus to release gonadotropin-releasing hormone.
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