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33-396: 57468 57138 ENSG00000124140 ENSMUSG00000017740 Q9H2X9 Q91V14 NM_020708 NM_001134771 NM_020333 NM_001355480 NM_001355481 NP_001128243 NP_065759 NP_065066 NP_001342409 NP_001342410 Potassium-chloride transporter member 5 (aka: KCC2 and SLC12A5) is a neuron-specific chloride potassium symporter responsible for establishing

66-445: A critical role in the structure and function of dendritic spines which host most excitatory synapses in cortical neurons. Through an interaction with actin cytoskeleton, KCC2 forms a molecular barrier to the diffusion of transmembrane proteins within dendritic spines, thereby regulating the local confinement of AMPA receptors and synaptic potency. It has been proposed that the downregulation of KCC2 observed following neuronal trauma, and

99-443: A developmental shift of the chloride ion concentration within neurons from high to low intracellular concentration. Effectively, as the chloride ion concentration is reduced, the chloride gradient across the cellular membrane is reversed such that GABA A receptor and glycine receptor stimulation causes chloride ion influx, making the internal neuronal environment more negative (i.e. more hyperpolarized ) than it would be at rest. This

132-403: A group of several symporters/antiporters that specifically allow only one charged hydrogen ion (more commonly known as a proton) and one charged K+ ion. This group of carriers all contribute to modulate the chemiosmotic potential inside the cell. Initially H+ is pumped into the area outside the root by H+ ATPase. This change in both the pH and electrochemical potential gradient between the inside of

165-543: A homeostatic process to compensate for the reduced GABA transmission due to altered chloride extrusion. Mutations in SLC12A5 are associated with colon cancer . KCC2 is transcriptionally downregulated following central nervous system injury by the TrkB receptor signalling transduction cascade (activated by BDNF and NT-4/5 ). It is conventionally thought that phosphorylation inactivates or downregulates KCC2, however there

198-411: A magnet together. Depending on the strength of the magnet, the repulsion may be so strong that it is impossible to push the magnets together unless aided by machinery. Proton-motive force does work on the system by bringing ions back towards the epidermis of the root or surface of a root hair along with the protons. From the surface of the soil/root interface, specific carriers, like H+/K+ symporters allow

231-509: A potassium ion (K ) and two chloride ions (2Cl ). Loop diuretics such as furosemide (Lasix) act on this protein. Marine invertebrates use symporters to transport against strong chemical gradients. Amino acids and sugars are taken up from sea water in the presence of extracellular sodium and is driven by the NA /K -ATPase pump. In the roots of plants , the H+/K+ symporters are only one member of

264-527: A separate gene of the solute carrier family 12, hence accounting for the numbers succeeding its name. For example, chloride potassium symporter 5, or KCC2, is expressed through the SLC12A5 gene. Notably, symporters prior to 4 in the same family are other types of ion pumps. SLC12A3, for instance, is the sodium-chloride symporter . This membrane protein –related article is a stub . You can help Misplaced Pages by expanding it . Symporters A symporter

297-445: 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 cell membrane at the same time, and is, therefore, a type of cotransporter . The transporter is called a symporter, because the molecules will travel in the same direction in relation to each other. This

330-475: Is crucial for classical postsynaptic inhibition through GABA A receptors and glycine receptors in the central nervous system. KCC2 utilizes the potassium gradient generated by the Na/K pump to drive chloride extrusion from neurons. In fact, any disruption of the neuronal K gradient would indirectly affect KCC2 activity. Loss of KCC2 following neuronal damage (i.e. ischemia , spinal cord damage, physical trauma to

363-441: Is drawn in alongside the ions. KCC2 may help to eliminate excess ions from the cell in order to re-establish osmotic homeostasis . KCC2 is a member of the cation-chloride cotransporter (CCC) superfamily of proteins. As with all CCC proteins, KCC2 is an integral membrane protein with 12 transmembrane domains and both N- and C-terminal cytoplasmic domains. The terminal cytoplasmic domains can be phosphorylated by kinases within

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396-459: Is drawn into neurons along with ionic solutes. This phenomenon is known as excitotoxicity. KCC2 has been shown to be activated by cell-swelling, and may therefore play a role in eliminating excess ions following periods of high stimulation in order to maintain steady-state neuronal volume and prevent cells from bursting. This role may also account for the fact that KCC2 has been known to colocalize near excitatory synapses, even though its primary role

429-426: Is evident by dropping a drop of food coloring in a glass of water. It does not aggregate, but begins to move from the highly concentrated areas (the colored areas) to the areas of low concentration (clear areas). Second, large groups of predominantly positively charged or negatively charged particles will naturally repel each other. This is demonstrated by attempting to push the two positive poles or two negative poles of

462-413: Is in contrast to the antiport transporter. Typically, the ion(s) will move down the electrochemical gradient, allowing the other molecule(s) to move against the concentration gradient. The movement of the ion(s) across the membrane is facilitated diffusion , and is coupled with the active transport of the molecule(s). In symport, two molecule move in a 'similar direction' at the 'same time'. For example,

495-451: Is in the public domain . Chloride potassium symporter The concentrations of K and Cl ions are high inside the cell due to the activities of Na /K ATPase and NKCC cotransporter , respectively. Hence, their net driving force acting on the K/Cl cotransporter favours the exit of both K and Cl from the cell. Chloride potassium symporter are classified into: Each is encoded by

528-599: Is recent evidence to suggest that phosphorylation at different sites on the KCC2 protein determines different regulational outcomes: KCC2 has an extremely high rate of turnover at the plasmalemma (minutes), suggesting that phosphorylation serves as the primary mechanism for rapid regulation. KCC2 is downregulated by excitatory glutamate activity on NMDA receptor activity and Ca influx. This process involves rapid dephosphorylation on Ser940 and calpain protease cleavage of KCC2, leading to enhanced membrane diffusion and endocytosis of

561-449: Is the developmental shift of inhibitory synapses from the excitatory postsynaptic responses of the early neural development phase to the inhibitory postsynaptic responses observed throughout maturity. Current literature suggests that KCC2 serves three primary roles within neurons: KCC2 is a potassium (K)/chloride (Cl) symporter that maintains chloride homeostasis in neurons. The electrochemical chloride gradient established by KCC2 activity

594-476: Is to establish the chloride gradient for postsynaptic inhibition. In addition to controlling the efficacy of GABAergic synapses through chloride homeostasis, KCC2 play a critical role in the morphogenesis and function of glutamatergic synapses within the central nervous system. Studies on hippocampal tissue in KCC2 knockout animals showed that neurons lacking KCC2 have stunted dendritic growth and malformed dendritic spines. Recent studies demonstrate that KCC2 plays

627-427: The SLC12A5 gene in humans. Animals with reduced expression of this transporter exhibit severe motor deficits, epileptiform activity, and spasticity. KCC2 knockout animals , in which KCC2 is completely absent, die postnatally due to respiratory failure. KCC2 is a neuron-specific membrane protein expressed throughout the central nervous system , including the hippocampus, hypothalamus, brainstem, and motoneurons of

660-400: The bloodstream. This is the basis of oral rehydration therapy . If this symporter did not exist, individual sodium channels and glucose uniporters would not be able to transfer glucose against the concentration gradient and into the bloodstream. Na /K /2Cl symporter in the loop of Henle in the renal tubules of the kidney transports 4 molecules of 3 different types; a sodium ion (Na ),

693-434: The cell and the outside produces a proton-motive force , as the protons will want to naturally flow back into the area of low concentration and with a voltage closer to zero from their current situation of being in an area of high concentration of positively charged protons. The reasons for this are twofold. For one, substances in nature have a tendency to move from areas of high concentration to areas of low concentration, as

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726-438: The central nervous system) results in the loss of inhibitory regulation and the subsequent development of neuronal hyperexcitability, motor spasticity, and seizure-like activity as GABA A receptors and glycine receptors revert from hyperpolarizing to depolarizing postsynaptic effects. High levels of stimulation and subsequent ionic influx through activated ion channels can result in cellular swelling as osmotically-obliged water

759-615: The chloride gradient is such that stimulation of GABA A receptors and glycine receptors at inhibitory synapses causes chloride ions to flow out of cells, making the internal neuronal environment less negative (i.e. more depolarized ) than it would be at rest. At this stage, GABA A receptors and glycine receptors act as excitatory rather than inhibitory effectors on postsynaptic neurons, resulting in depolarization and hyperexcitability of neural networks. During postnatal development, KCC2 levels are strongly upregulated while NKCC1 levels are down regulated. This change in expression correlates to

792-437: The chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a critical mediator of synaptic inhibition , cellular protection against excitotoxicity and may also act as a modulator of neuroplasticity . Potassium-chloride transporter member 5 is also known by the names: KCC2 (potassium chloride cotransporter 2) for its ionic substrates, and SLC12A5 for its genetic origin from

825-416: The consequent depolarizing shift of GABA A -mediated synapses, may be an aspect of neuronal de-differentiation. De-differentiation of damaged portions of the nervous system would allow for neuronal networks to return to higher levels of plasticity in order to rewire surviving neurons to compensate for damage in the network. In addition, reduced glutamatergic transmission upon KCC2 downregulation may serve as

858-425: The hyperpolarizing influx of chloride ions to inhibit postsynaptic neurons from firing. Counterintuitively, KCC2 has also been shown to colocalize at excitatory synapses . One suggested explanation for such colocalization is a potential protective role of KCC2 against excitotoxicity. Ion influx due to the excitatory synaptic stimulation of ion channels in the neuronal membrane causes osmotic swelling of cells as water

891-421: The movement of glucose along with sodium ions. It exploits the uphill movement of other molecules from low to high concentration, which is against the electrochemical gradient for the transport of solute molecules downhill from higher to lower concentration. SGLT1 in the intestinal epithelium transports sodium ions (Na ) and glucose across luminal membrane of the epithelial cells so that it can be absorbed into

924-466: The neuron for rapid regulation. There are two isoforms of KCC2: KCC2a and KCC2b. The two isoforms arise from alternative promoters on the SLC12A5 gene and differential splicing of the first mRNA exon. The isoforms differ in their N-termini, with the KCC2a form constituting the larger of the two splice variants. KCC2a levels remain relatively constant during pre- and postnatal development. KCC2b, on

957-524: The oligomer to monomer ratio increases in correlation to the development of the chloride ion gradient in neurons. KCC2 levels are low during mammalian embryonic development, when neural networks are still being established and neurons are highly plastic (changeable). During this stage, intracellular chloride ion concentrations are high due to low KCC2 expression and high levels of a transporter known as NKCC1 (Na/K chloride cotransporter 1), which moves chloride ions into cells. Thus, during embryonic development,

990-448: The other hand, is scarcely present during prenatal development and is strongly upregulated during postnatal development. The upregulation of KCC2b expression is thought to be responsible for the “developmental shift” observed in mammals from depolarizing postsynaptic effects of inhibitory synapses in early neural networks to hyperpolarizing effects in mature neural networks. KCC2b knockout mice can survive up to postnatal day 17 (P17) due to

1023-572: The presence of functional KCC2a alone, but they exhibit low body weight, motor deficits and generalized seizures. Complete KCC2 knockouts (both KCC2a and KCC2b absent) die after birth due to respiratory failure. Both KCC2 isoforms can form homomultimers, or heteromultimers with other K-Cl symporters on the cell membrane to maintain chloride homeostasis in neurons. Dimers, trimers, and tetramers involving KCC2 have been identified in brainstem neurons. Oligomerization may play an important role in transporter function and activation, as it has been observed that

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1056-538: The transporter, as demonstrated in experiments using single particle tracking . Glutamate release occurs not only at excitatory synapses, but is also known to occur after neuronal damage or ischemic insult. Thus, activity-dependent downregulation may be the underlying mechanism by which KCC2 downregulation occurs following central nervous system injury. This article incorporates text from the United States National Library of Medicine , which

1089-405: The ventral spinal cord. At the subcellular level, KCC2 has been found in membranes of the somata and dendrites of neurons, with no evidence of expression on axons . KCC2 has also been shown to colocalize with GABA A receptors , which serve as ligand-gated ion channels to allow chloride ion movement across the cell membrane. Under normal conditions, the opening of GABA A receptors permits

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