PMID-sentid Pub_year Sent_text comp_official_name comp_offsetprotein_name organism prot_offset 33239270-5 2021 We therefore determined the net effects of KCC2 transport activity on cytoplasmic chloride elevation and Cl- extrusion rates during spontaneous recurrent ictal-like epileptiform discharges (ILDs) in organotypic hippocampal slices in vitro, as well as the correlation between ionic and electrographic effects. Chlorides 82-90 solute carrier family 12 member 5 Homo sapiens 43-47 33640193-1 2021 KCC2, best known as the neuron-specific chloride-extruder that sets the strength and polarity of GABAergic currents during neuronal maturation, is a multifunctional molecule that can regulate cytoskeletal dynamics via its C-terminal domain (CTD). Chlorides 40-48 solute carrier family 12 member 5 Homo sapiens 0-4 33239270-7 2021 In contrast, the putative KCC2 upregulator CLP257 improved chloride homeostasis and reduced the duration and frequency of ILDs in a concentration-dependent manner. Chlorides 59-67 solute carrier family 12 member 5 Homo sapiens 26-30 33239270-9 2021 Anticonvulsant effects predominate when KCC2-mediated chloride transport rather than potassium buffering is the rate-limiting step in restoring ECl and the efficacy of GABAergic inhibition during recurrent ILDs.Significance Statement In an in vitro preparation that generates spontaneous ictal-like epileptiform discharges (ILDs), we measured the effects of acute KCC2 modulation on both neuronal chloride and ILD activity. Chlorides 54-62 solute carrier family 12 member 5 Homo sapiens 40-44 33239270-9 2021 Anticonvulsant effects predominate when KCC2-mediated chloride transport rather than potassium buffering is the rate-limiting step in restoring ECl and the efficacy of GABAergic inhibition during recurrent ILDs.Significance Statement In an in vitro preparation that generates spontaneous ictal-like epileptiform discharges (ILDs), we measured the effects of acute KCC2 modulation on both neuronal chloride and ILD activity. Chlorides 397-405 solute carrier family 12 member 5 Homo sapiens 40-44 33239270-12 2021 These findings regarding the role of KCC2 on baseline chloride, chloride elevations during ILD activity, Cl- extrusion rates and ILD activity resolve conflicting reports in the literature, provide a coherent understanding of the role KCC2 activity in chloride homeostasis during ILDs, and support the feasibility of developing KCC2 modulators into sorely-needed anticonvulsant medications. Chlorides 54-62 solute carrier family 12 member 5 Homo sapiens 37-41 33239270-12 2021 These findings regarding the role of KCC2 on baseline chloride, chloride elevations during ILD activity, Cl- extrusion rates and ILD activity resolve conflicting reports in the literature, provide a coherent understanding of the role KCC2 activity in chloride homeostasis during ILDs, and support the feasibility of developing KCC2 modulators into sorely-needed anticonvulsant medications. Chlorides 64-72 solute carrier family 12 member 5 Homo sapiens 37-41 33239270-12 2021 These findings regarding the role of KCC2 on baseline chloride, chloride elevations during ILD activity, Cl- extrusion rates and ILD activity resolve conflicting reports in the literature, provide a coherent understanding of the role KCC2 activity in chloride homeostasis during ILDs, and support the feasibility of developing KCC2 modulators into sorely-needed anticonvulsant medications. Chlorides 64-72 solute carrier family 12 member 5 Homo sapiens 37-41 33266310-1 2020 Intracellular chloride levels in the brain are regulated primarily through the opposing effects of two cation-chloride co-transporters (CCCs), namely K+-Cl- co-transporter-2 (KCC2) and Na+-K+-Cl- co-transporter-1 (NKCC1). Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 150-173 33266310-1 2020 Intracellular chloride levels in the brain are regulated primarily through the opposing effects of two cation-chloride co-transporters (CCCs), namely K+-Cl- co-transporter-2 (KCC2) and Na+-K+-Cl- co-transporter-1 (NKCC1). Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 175-179 32769979-1 2020 GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). Chlorides 79-87 solute carrier family 12 member 5 Homo sapiens 141-164 32892950-2 2020 GABAAR function is dependent on its expression, distribution, and the chloride (Cl-) transmembrane gradient, which is determined by the potassium-chloride cotransporter 2 (KCC2) in the adult brain. Chlorides 70-78 solute carrier family 12 member 5 Homo sapiens 172-176 32769979-1 2020 GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). Chlorides 79-87 solute carrier family 12 member 5 Homo sapiens 166-170 30871970-0 2020 KCC2 membrane diffusion tunes neuronal chloride homeostasis. Chlorides 39-47 solute carrier family 12 member 5 Homo sapiens 0-4 32359429-4 2020 Analysis of the naked mole-rat genome revealed, uniquely among mammals, a histidine point variation in the neuronal potassium-chloride cotransporter 2 (KCC2). Chlorides 126-134 solute carrier family 12 member 5 Homo sapiens 152-156 30871970-1 2020 Neuronal Cl- homeostasis is regulated by the activity of two cation chloride co-transporters (CCCs), the K+-Cl- cotransporter KCC2 and the Na+-K+-Cl- cotransporter NKCC1, which are primarily extruding and importing chloride in neurons, respectively. Chlorides 68-76 solute carrier family 12 member 5 Homo sapiens 126-130 31174368-5 2019 Firstly, APP is shown to interact with and modulate the levels and activity of the neuron-specific Potassium-Chloride (K+-Cl-) cotransporter KCC2/SLC12A5. Chlorides 109-117 solute carrier family 12 member 5 Homo sapiens 146-153 32064760-1 2020 KCC2, encoded in humans by the SLC12A5 gene, is a multifunctional neuron-specific protein initially identified as the chloride (Cl- ) extruder critical for hyperpolarizing GABAA receptor currents. Chlorides 118-126 solute carrier family 12 member 5 Homo sapiens 0-4 32064760-1 2020 KCC2, encoded in humans by the SLC12A5 gene, is a multifunctional neuron-specific protein initially identified as the chloride (Cl- ) extruder critical for hyperpolarizing GABAA receptor currents. Chlorides 118-126 solute carrier family 12 member 5 Homo sapiens 31-38 32078115-8 2020 Caffeine decreased the levels of the chloride co-transporter KCC2 and delayed the developmental shift on GABAA receptor response from depolarizing to hyperpolarizing. Chlorides 37-45 solute carrier family 12 member 5 Homo sapiens 61-65 31930378-1 2020 The GABA response switch from excitatory to inhibitory is a key event in neuronal maturation that depends on the regulated expression of chloride transporters NKCC1 and KCC2. Chlorides 137-145 solute carrier family 12 member 5 Homo sapiens 169-173 31315039-0 2019 Chloride Dysregulation through Downregulation of KCC2 Mediates Neuropathic Pain in Both Sexes. Chlorides 0-8 solute carrier family 12 member 5 Homo sapiens 49-53 31315039-5 2019 We find that inhibiting KCC2 in uninjured animals reproduces behavioral and electrophysiological features of neuropathic pain in both sexes and, consistent with equivalent injury-induced downregulation of KCC2, that counteracting chloride dysregulation reverses injury-induced behavioral and electrophysiological changes in both sexes. Chlorides 230-238 solute carrier family 12 member 5 Homo sapiens 24-28 31315039-5 2019 We find that inhibiting KCC2 in uninjured animals reproduces behavioral and electrophysiological features of neuropathic pain in both sexes and, consistent with equivalent injury-induced downregulation of KCC2, that counteracting chloride dysregulation reverses injury-induced behavioral and electrophysiological changes in both sexes. Chlorides 230-238 solute carrier family 12 member 5 Homo sapiens 205-209 31315039-7 2019 Whereas diverse (and sexually dimorphic) mechanisms regulate KCC2, regulation of intracellular chloride relies almost exclusively on KCC2. Chlorides 95-103 solute carrier family 12 member 5 Homo sapiens 133-137 32322187-2 2020 Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na+-K+-2Cl- cotransporter 1 (NKCC1) and K+-Cl- cotransporter 2 (KCC2). Chlorides 44-52 solute carrier family 12 member 5 Homo sapiens 137-159 32322187-2 2020 Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na+-K+-2Cl- cotransporter 1 (NKCC1) and K+-Cl- cotransporter 2 (KCC2). Chlorides 44-52 solute carrier family 12 member 5 Homo sapiens 161-165 32010056-2 2019 The Na-K-2Cl cotransporter isoform 1 (NKCC1) and the K-Cl cotransporter isoform 2 (KCC2) are two main cation-chloride cotransporters (CCCs) that have been implicated in human epilepsy. Chlorides 109-117 solute carrier family 12 member 5 Homo sapiens 53-81 32010056-2 2019 The Na-K-2Cl cotransporter isoform 1 (NKCC1) and the K-Cl cotransporter isoform 2 (KCC2) are two main cation-chloride cotransporters (CCCs) that have been implicated in human epilepsy. Chlorides 109-117 solute carrier family 12 member 5 Homo sapiens 83-87 31826658-0 2020 KCC2 Much Chloride Might Not Be the Only Problem. Chlorides 10-18 solute carrier family 12 member 5 Homo sapiens 0-4 31806759-6 2019 The signaling pathway linking 5-HT2AR activation and normalization of KCC2 function was dependent on protein kinase C signaling and phosphorylation of KCC2 at serine 940 (S940), as mutation of S940 to alanine prevented restoration of chloride transport function by TCB-2. Chlorides 234-242 solute carrier family 12 member 5 Homo sapiens 70-74 31806759-6 2019 The signaling pathway linking 5-HT2AR activation and normalization of KCC2 function was dependent on protein kinase C signaling and phosphorylation of KCC2 at serine 940 (S940), as mutation of S940 to alanine prevented restoration of chloride transport function by TCB-2. Chlorides 234-242 solute carrier family 12 member 5 Homo sapiens 151-155 31803025-3 2019 Type 2 K+-Cl- cotransporter (KCC2), encoded by SLC12A5, is important for chloride homeostasis and neuronal excitability. Chlorides 73-81 solute carrier family 12 member 5 Homo sapiens 29-33 31803025-3 2019 Type 2 K+-Cl- cotransporter (KCC2), encoded by SLC12A5, is important for chloride homeostasis and neuronal excitability. Chlorides 73-81 solute carrier family 12 member 5 Homo sapiens 47-54 30417726-2 2019 The potassium chloride co-transporter (KCC2) plays a central role in intracellular chloride homeostasis and the inhibitory function of mature neurons. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 39-43 30590202-1 2019 Spinal chloride-dependent synaptic inhibition is critical in regulating breathing and requires neuronal chloride gradients established by cation-chloride cotransporters Na+-K+-2Cl- (NKCC1) and K+-Cl- (KCC2). Chlorides 7-15 solute carrier family 12 member 5 Homo sapiens 201-205 30784026-1 2019 BACKGROUND: Dysregulation of cation-chloride cotransporters NKCC1 and KCC2 expression was shown to be related to drug-resistant epilepsy. Chlorides 36-44 solute carrier family 12 member 5 Homo sapiens 70-74 30590202-1 2019 Spinal chloride-dependent synaptic inhibition is critical in regulating breathing and requires neuronal chloride gradients established by cation-chloride cotransporters Na+-K+-2Cl- (NKCC1) and K+-Cl- (KCC2). Chlorides 104-112 solute carrier family 12 member 5 Homo sapiens 201-205 30406192-2 2018 The potassium chloride cotransporter KCC2, which serves to maintain low intraneuronal Cl- concentration and thus render chloride-mediated synaptic signaling inhibitory, exists in two isoforms, KCC2a and KCC2b. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 37-41 30169756-1 2018 KCC2 is the major chloride extruder in neurons. Chlorides 18-26 solute carrier family 12 member 5 Homo sapiens 0-4 29729285-2 2018 This regulation is mainly dependent on the two co-transporters K+/Cl- co-transporter KCC2 and Na+/K+/Cl- co-transporter NKCC1, whose activity can decrease or increase neuronal chloride concentrations respectively. Chlorides 176-184 solute carrier family 12 member 5 Homo sapiens 85-89 29782876-5 2018 Chloride homeostasis can be regulated by Cl- cotransporters like NKCC1 and KCC2 in the membrane, but the mechanisms for maintaining [Cl-]i are still under debate. Chlorides 0-8 solute carrier family 12 member 5 Homo sapiens 75-79 28677029-6 2018 The alteration of KCC2 expression affects GABAergic and glycinergic neurotransmissions, because KCC2 is a potassium-chloride exporter and serves to maintain intracellular chloride concentration. Chlorides 116-124 solute carrier family 12 member 5 Homo sapiens 18-22 29218745-4 2018 The chloride reversal potential is determined, in part, by the expression level of a neuron-specific potassium-chloride cotransporter, KCC2, which is developmentally upregulated in mammals. Chlorides 4-12 solute carrier family 12 member 5 Homo sapiens 135-139 28677029-6 2018 The alteration of KCC2 expression affects GABAergic and glycinergic neurotransmissions, because KCC2 is a potassium-chloride exporter and serves to maintain intracellular chloride concentration. Chlorides 116-124 solute carrier family 12 member 5 Homo sapiens 96-100 28677029-6 2018 The alteration of KCC2 expression affects GABAergic and glycinergic neurotransmissions, because KCC2 is a potassium-chloride exporter and serves to maintain intracellular chloride concentration. Chlorides 171-179 solute carrier family 12 member 5 Homo sapiens 18-22 28677029-6 2018 The alteration of KCC2 expression affects GABAergic and glycinergic neurotransmissions, because KCC2 is a potassium-chloride exporter and serves to maintain intracellular chloride concentration. Chlorides 171-179 solute carrier family 12 member 5 Homo sapiens 96-100 29184062-1 2017 KCC2 is a neuron specific K+-Cl- co-transporter that controls neuronal chloride homeostasis, and is critically involved in many neurological diseases including brain trauma, epilepsies, autism and schizophrenia. Chlorides 71-79 solute carrier family 12 member 5 Homo sapiens 0-4 28450542-0 2017 Neuronal Chloride Regulation via KCC2 Is Modulated through a GABAB Receptor Protein Complex. Chlorides 9-17 solute carrier family 12 member 5 Homo sapiens 33-37 28888841-1 2017 The neuron-specific K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the fast hyperpolarizing responses of the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine. Chlorides 76-84 solute carrier family 12 member 5 Homo sapiens 39-43 29176664-1 2017 The K+-Cl- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl-]i. Chlorides 132-140 solute carrier family 12 member 5 Homo sapiens 26-30 29176664-1 2017 The K+-Cl- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl-]i. Chlorides 132-140 solute carrier family 12 member 5 Homo sapiens 32-39 28803659-3 2017 Hyperpolarizing inhibition mediated by type A GABA (GABAA) receptors is dependent on chloride extrusion by the neuron-specific type 2K+-Cl- cotransporter (KCC2). Chlorides 85-93 solute carrier family 12 member 5 Homo sapiens 155-159 28450542-3 2017 Here we report that GABAB receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride-permeable ionotropic GABAA receptor in mature neurons. Chlorides 80-88 solute carrier family 12 member 5 Homo sapiens 112-116 28450542-8 2017 This association is significant because KCC2 sets the intracellular chloride concentration found in mature neurons and thereby establishes the driving force for the chloride-permeable GABAAR. Chlorides 68-76 solute carrier family 12 member 5 Homo sapiens 40-44 28450542-8 2017 This association is significant because KCC2 sets the intracellular chloride concentration found in mature neurons and thereby establishes the driving force for the chloride-permeable GABAAR. Chlorides 165-173 solute carrier family 12 member 5 Homo sapiens 40-44 28450542-9 2017 We demonstrate that GABABR activation can regulate KCC2 at the cell surface in a manner that alters intracellular chloride and the reversal potential for the GABAAR. Chlorides 114-122 solute carrier family 12 member 5 Homo sapiens 51-55 27852771-3 2016 KCC2 regulates intraneuronal chloride and extracellular potassium levels by extruding both ions. Chlorides 29-37 solute carrier family 12 member 5 Homo sapiens 0-4 28057537-3 2017 Na+-K+-2Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating intracellular chloride concentrations. Chlorides 154-162 solute carrier family 12 member 5 Homo sapiens 41-64 28057537-3 2017 Na+-K+-2Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating intracellular chloride concentrations. Chlorides 154-162 solute carrier family 12 member 5 Homo sapiens 66-70 27881775-2 2016 Our model contains Hodgkin-Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. Chlorides 160-168 solute carrier family 12 member 5 Homo sapiens 146-150 28333147-1 2017 Solute carrier family 12 member 5 (SLC12A5), an integral membrane KCl cotransporter, which maintains chloride homeostasis in neurons, is aberrantly expressed and involved in the tumorigenesis of certain cancers. Chlorides 101-109 solute carrier family 12 member 5 Homo sapiens 0-33 28333147-1 2017 Solute carrier family 12 member 5 (SLC12A5), an integral membrane KCl cotransporter, which maintains chloride homeostasis in neurons, is aberrantly expressed and involved in the tumorigenesis of certain cancers. Chlorides 101-109 solute carrier family 12 member 5 Homo sapiens 35-42 27852771-4 2016 Absence of effective KCC2 may alter the dynamics of chloride and potassium levels during repeated activation of GABAergic synapses due to interneuron activity. Chlorides 52-60 solute carrier family 12 member 5 Homo sapiens 21-25 27852771-9 2016 The pyramidal cell model explicitly incorporated the cotransporter KCC2 and its effects on the internal/external chloride and potassium levels. Chlorides 113-121 solute carrier family 12 member 5 Homo sapiens 67-71 27852771-10 2016 Our network model suggested the loss of KCC2 in a critical number of pyramidal cells increased external potassium and intracellular chloride concentrations leading to seizure-like field potential oscillations. Chlorides 132-140 solute carrier family 12 member 5 Homo sapiens 40-44 26427846-2 2016 The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role in determining the polarity of GABAA receptor-mediated chloride currents. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 40-44 27513374-10 2016 These findings support a mechanism of tumor-associated epilepsy involving downregulation of KCC2 in the peritumoral region leading to compromised GABAergic inhibition and suggest that modulating chloride homeostasis may be useful for seizure control. Chlorides 195-203 solute carrier family 12 member 5 Homo sapiens 92-96 27002180-6 2016 In recent years, it has also become apparent that intra-neuronal chloride concentration is partially regulated by cation-chloride co-transporters (CCCs), in particular NKCC1 and KCC2. Chlorides 65-73 solute carrier family 12 member 5 Homo sapiens 178-182 26427846-2 2016 The potassium-chloride cotransporter-2 (KCC2) is the main chloride extruder in neurons and hence will play a prominent role in determining the polarity of GABAA receptor-mediated chloride currents. Chlorides 58-66 solute carrier family 12 member 5 Homo sapiens 40-44 25843644-7 2015 The correlation between EGABA and NH4(+)-induced pHi shifts enabled an estimate of the range of chloride extrusion possible by kinase/phosphatase regulation of KCC2. Chlorides 96-104 solute carrier family 12 member 5 Homo sapiens 160-164 26506510-2 2016 Among them the Na(+) -K(+) -2Cl(-) co-transporter (NKCC1) is responsible for intracellular chloride accumulation in most immature brain structures, whereas the K(+) -Cl(-) co-transporter (KCC2) extrudes chloride from mature neurons, ensuring chloride-mediated inhibitory effects of GABA/glycine. Chlorides 91-99 solute carrier family 12 member 5 Homo sapiens 188-192 26780567-3 2016 At the same time period of postnatal development, the transmembrane chloride gradient is changed due to increased expression of the potassium-chloride cotransporter (KCC2), thereby shifting the GABA- and glycine-mediated synaptic currents from mostly excitatory depolarization to inhibitory hyperpolarization. Chlorides 68-76 solute carrier family 12 member 5 Homo sapiens 166-170 29143559-3 2016 KCC2 levels are developmentally regulated, and a postnatal upregulation of KCC2 generates a low intracellular chloride concentration that allows the neurotransmitters gamma-aminobutyric acid (GABA) and glycine to exert inhibitory neurotransmission through its Cl- permeating channel. Chlorides 110-118 solute carrier family 12 member 5 Homo sapiens 75-79 26558388-11 2015 Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum. Chlorides 26-34 solute carrier family 12 member 5 Homo sapiens 78-82 26388734-6 2015 With extrusion of chloride by KCC2, the Cl(-) reversal potential shifts and GABA and glycine responses become inhibitory. Chlorides 18-26 solute carrier family 12 member 5 Homo sapiens 30-34 26858607-0 2015 Mild KCC2 Hypofunction Causes Inconspicuous Chloride Dysregulation that Degrades Neural Coding. Chlorides 44-52 solute carrier family 12 member 5 Homo sapiens 5-9 26333769-1 2015 The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 38-42 26333769-1 2015 The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 55-62 25843644-10 2015 Our findings highlight the significant potential for regulating the inhibitory tone by KCC2-mediated chloride extrusion and suggest that cellular signaling pathways may act combinatorially to alter KCC2 phosphorylation/dephosphorylation and thereby tune the strength of synaptic inhibition. Chlorides 101-109 solute carrier family 12 member 5 Homo sapiens 87-91 25834055-1 2015 In healthy mature motoneurons (MNs), KCC2 cotransporters maintain the intracellular chloride concentration at low levels, a prerequisite for postsynaptic inhibition mediated by GABA and glycine. Chlorides 84-92 solute carrier family 12 member 5 Homo sapiens 37-41 26056138-1 2015 Chloride extrusion in mature neurons is largely mediated by the neuron-specific potassium-chloride cotransporter KCC2. Chlorides 0-8 solute carrier family 12 member 5 Homo sapiens 113-117 26056138-2 2015 In addition, independently of its chloride transport function, KCC2 regulates the development and morphology of dendritic spines through structural interactions with the actin cytoskeleton. Chlorides 34-42 solute carrier family 12 member 5 Homo sapiens 63-67 26043076-4 2015 The results identify a threonine- and tyrosine-phosphorylation-resistant KCC2 variant with increased chloride transport activity, but they also identify the KCC2 N-terminal domain (NTD) as the relevant minimal KCC2 protein domain that is sufficient for neuroprotection. Chlorides 101-109 solute carrier family 12 member 5 Homo sapiens 73-77 25878279-6 2015 In neuropathic pain, GABAAR-mediated signaling can be further disrupted by the loss of the KCC2 chloride anion gradient. Chlorides 96-110 solute carrier family 12 member 5 Homo sapiens 91-95 25834055-2 2015 KCC2 expression in lumbar MNs is reduced after spinal cord injury (SCI) resulting in a depolarizing shift of the chloride equilibrium potential. Chlorides 113-121 solute carrier family 12 member 5 Homo sapiens 0-4 23226777-0 2012 Changes in expression of the chloride homeostasis-regulating genes, KCC2 and NKCC1, in the blood of cirrhotic patients with hepatic encephalopathy. Chlorides 29-37 solute carrier family 12 member 5 Homo sapiens 68-72 24909111-2 2015 The K-Cl cotransport by KCC2 is central for hyperpolarizing inhibitory signaling, which is based on chloride currents mediated by gamma-aminobutyric acid (GABA)- or glycine-gated receptor channels. Chlorides 100-108 solute carrier family 12 member 5 Homo sapiens 24-28 25086309-2 2014 In the human epileptogenic neocortex an impaired chloride (Cl(-)) gradient has been proposed, due to decreases of potassium-coupled chloride transport (KCC2) and voltage-gated Cl(-) channels (ClC). Chlorides 49-57 solute carrier family 12 member 5 Homo sapiens 152-156 25072038-2 2014 This depends on accumulation of chloride inside the cell via the cation-chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. Chlorides 32-40 solute carrier family 12 member 5 Homo sapiens 143-147 25072038-2 2014 This depends on accumulation of chloride inside the cell via the cation-chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. Chlorides 72-80 solute carrier family 12 member 5 Homo sapiens 143-147 25072038-3 2014 The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. Chlorides 73-81 solute carrier family 12 member 5 Homo sapiens 44-48 24987336-4 2014 Recent evidence demonstrates that large inhibitory postsynaptic currents (IPSCs) in neurons of the superior paraolivary nucleus (SPN) are enhanced by a very low intracellular chloride concentration, generated by the neuronal potassium chloride co-transporter (KCC2) expressed in the postsynaptic neurons. Chlorides 175-183 solute carrier family 12 member 5 Homo sapiens 260-264 23964205-1 2013 Early in development, gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. Chlorides 189-197 solute carrier family 12 member 5 Homo sapiens 295-299 23964205-2 2013 The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. Chlorides 61-69 solute carrier family 12 member 5 Homo sapiens 22-26 23964205-2 2013 The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. Chlorides 123-131 solute carrier family 12 member 5 Homo sapiens 22-26 26312907-6 2015 We therefore investigated whether phosphorylation can allow KCC2 to achieve distinct levels of intracellular chloride ion concentrations in neurons. Chlorides 109-117 solute carrier family 12 member 5 Homo sapiens 60-64 26312907-9 2015 The correlation between reversal potential of GABAergic currents (EGABA) and NH4(+)-induced pHi shifts enabled an estimate of the range of chloride extrusion possible by kinase-phosphatase regulation of KCC2. Chlorides 139-147 solute carrier family 12 member 5 Homo sapiens 203-207 26312907-13 2015 INTERPRETATION: Our findings highlight the considerable potential for regulating the inhibitory tone by KCC2-mediated chloride extrusion. Chlorides 118-126 solute carrier family 12 member 5 Homo sapiens 104-108 24802699-5 2014 Newer approaches including isoform-specific NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2-mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment. Chlorides 181-189 solute carrier family 12 member 5 Homo sapiens 158-162 24615367-0 2014 Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter KCC2-mediated chloride extrusion in peripheral neuropathic pain. Chlorides 84-92 solute carrier family 12 member 5 Homo sapiens 107-111 24615367-2 2014 Maladaptive changes in chloride homeostasis due to a decrease in the functional expression of the potassium-chloride cotransporter KCC2 in spinal cord dorsal horn neurons are a major contributor to the central disinhibition of gamma-aminobutyric acid type A receptor- and glycine receptor-mediated signaling that characterizes neuropathic pain. Chlorides 23-31 solute carrier family 12 member 5 Homo sapiens 131-135 24615367-3 2014 A compelling novel analgesic strategy is to restore spinal ionotropic inhibition by enhancing KCC2-mediated chloride extrusion. Chlorides 108-116 solute carrier family 12 member 5 Homo sapiens 94-98 24615367-5 2014 Exploiting the chloride-dependent functional plasticity of the gamma-aminobutyric acid and glycinergic system by targeting KCC2 may be a tenable method of restoring ionotropic inhibition not only in neuropathic pain but also in other "hyperexcitable" diseases of the nervous system such as seizures and spasticity. Chlorides 15-23 solute carrier family 12 member 5 Homo sapiens 123-127 24225328-8 2014 Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Chlorides 55-63 solute carrier family 12 member 5 Homo sapiens 101-105 24071811-6 2013 One critical contributor to the neuronal chloride shift is the concomitant upregulation of expression of the chloride-extruding transporter molecule, KCC2. Chlorides 41-49 solute carrier family 12 member 5 Homo sapiens 150-154 23341142-3 2013 By making whole-cell recordings, we found that the effect of BDNF is mediated by neuronal potassium and chloride transporter KCC2 because it is blocked by inhibitors of KCC2 or by raising the intracellular chloride concentration. Chlorides 104-112 solute carrier family 12 member 5 Homo sapiens 125-129 23341142-3 2013 By making whole-cell recordings, we found that the effect of BDNF is mediated by neuronal potassium and chloride transporter KCC2 because it is blocked by inhibitors of KCC2 or by raising the intracellular chloride concentration. Chlorides 104-112 solute carrier family 12 member 5 Homo sapiens 169-173 25206700-1 2013 The Na(+)-K(+)-Cl(-) cotransporter 1 and K(+)-Cl(-) cotransporter 2 regulate the levels of intracellular chloride in hippocampal cells. Chlorides 105-113 solute carrier family 12 member 5 Homo sapiens 4-67 22854961-0 2012 N-methyl-D-aspartate receptor- and calpain-mediated proteolytic cleavage of K+-Cl- cotransporter-2 impairs spinal chloride homeostasis in neuropathic pain. Chlorides 114-122 solute carrier family 12 member 5 Homo sapiens 76-98 22854961-7 2012 Thus, nerve injury promotes proteolytic cleavage of KCC2 through NMDA receptor-calpain activation, resulting in disruption of chloride homeostasis and diminished synaptic inhibition in the spinal cord. Chlorides 126-134 solute carrier family 12 member 5 Homo sapiens 52-56 22363264-2 2012 By regulating intraneuronal chloride homeostasis, KCC2 strongly influences the efficacy and polarity of the chloride-permeable gamma-aminobutyric acid (GABA) type A and glycine receptor (GlyR) mediated synaptic transmission. Chlorides 28-36 solute carrier family 12 member 5 Homo sapiens 50-54 22363264-2 2012 By regulating intraneuronal chloride homeostasis, KCC2 strongly influences the efficacy and polarity of the chloride-permeable gamma-aminobutyric acid (GABA) type A and glycine receptor (GlyR) mediated synaptic transmission. Chlorides 108-116 solute carrier family 12 member 5 Homo sapiens 50-54 20086212-1 2010 KCC2, potassium chloride cotransporter 2, is expressed exclusively in the CNS (on inhibitory neurons) and plays a major role in maintaining appropriately low intracellular chloride levels that ensure inhibitory actions of GABA(A) and glycine receptors. Chlorides 16-24 solute carrier family 12 member 5 Homo sapiens 0-4 21042953-1 2011 Early in postnatal life gamma-aminobutyric acid (GABA), the primary inhibitory transmitter in adults, excites targeted neurons by an outwardly directed flux of chloride which results from the unbalance between the cation-chloride cotransporters NKCC1 and KCC2, involved in chloride uptake and extrusion, respectively. Chlorides 160-168 solute carrier family 12 member 5 Homo sapiens 255-259 20653959-5 2010 This involves an alteration in the chloride equilibrium potential as a result of down regulation of the potassium-chloride exporter, KCC2. Chlorides 35-43 solute carrier family 12 member 5 Homo sapiens 133-137 23071770-3 2012 In particular, the interplay intracellular chloride accumulation via the GABA(A) receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABA(A)-mediated excitation is complex. Chlorides 43-51 solute carrier family 12 member 5 Homo sapiens 159-163 21911617-2 2011 Unlike other ubiquitously expressed KCC isoforms, expression of KCC2 is widely considered to be restricted to neurons, where it is responsible for maintaining a low intracellular chloride concentration to drive hyperpolarising postsynaptic responses to the inhibitory neurotransmitters GABA and glycine. Chlorides 179-187 solute carrier family 12 member 5 Homo sapiens 64-68 21878564-1 2011 The K-Cl cotransporter KCC2 plays an essential role in neuronal chloride homeostasis, and thereby influences the efficacy and polarity of GABA signaling. Chlorides 64-72 solute carrier family 12 member 5 Homo sapiens 23-27 20819979-3 2011 In the central nervous system, the intracellular chloride level is determined by the activity of 2 cation-chloride transporters, NKCC1 and KCC2. Chlorides 49-57 solute carrier family 12 member 5 Homo sapiens 139-143 20819979-14 2011 CONCLUSION: In schizophrenia, increased expression levels, and possibly increased kinase activities, of OXSR1 and WNK3 may shift the balance of chloride transport by NKCC1 and KCC2 and alter the nature of gamma-aminobutyric acid neurotransmission in the prefrontal cortex. Chlorides 144-152 solute carrier family 12 member 5 Homo sapiens 176-180 21333799-2 2011 The postsynaptic action depends on the intracellular concentration of chloride ions ([Cl(-)](i)), which is regulated by proteins in the plasma membrane: the K(+)-Cl(-) cotransporter KCC2 and the Na(+)-K(+)-Cl(-) cotransporter NKCC1, which extrude and intrude Cl(-) ions, respectively. Chlorides 70-78 solute carrier family 12 member 5 Homo sapiens 182-186 19923298-0 2009 Novel repression of Kcc2 transcription by REST-RE-1 controls developmental switch in neuronal chloride. Chlorides 94-102 solute carrier family 12 member 5 Homo sapiens 20-24 19923298-1 2009 Transcriptional upregulation of Kcc2b, the gene variant encoding the major isoform of the KCC2 chloride transporter, underlies a rapid perinatal decrease in intraneuronal chloride concentration (chloride shift), which is necessary for GABA to act inhibitory. Chlorides 95-103 solute carrier family 12 member 5 Homo sapiens 90-94 18772206-1 2008 The furosemide-sensitive potassium-chloride cotransporter (KCC2) plays an important role in establishing the intracellular chloride concentration in many neurons within the central nervous system. Chlorides 35-43 solute carrier family 12 member 5 Homo sapiens 59-63 19675228-1 2009 Chloride influx through GABA-gated chloride channels, the primary mechanism by which neural activity is inhibited in the adult mammalian brain, depends on chloride gradients established by the potassium chloride cotransporter KCC2. Chlorides 0-8 solute carrier family 12 member 5 Homo sapiens 226-230 19675228-1 2009 Chloride influx through GABA-gated chloride channels, the primary mechanism by which neural activity is inhibited in the adult mammalian brain, depends on chloride gradients established by the potassium chloride cotransporter KCC2. Chlorides 35-43 solute carrier family 12 member 5 Homo sapiens 226-230 19307176-1 2009 The neuron-specific K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the fast hyperpolarizing actions of inhibitory neurotransmitters. Chlorides 76-84 solute carrier family 12 member 5 Homo sapiens 39-43 18772206-4 2008 Specifically, group I mGluRs signal via activation of a protein kinase C-dependent pathway to alter KCC2 activity, thereby altering the intracellular chloride concentration, and thus inhibitory synaptic input. Chlorides 150-158 solute carrier family 12 member 5 Homo sapiens 100-104 18772206-5 2008 This interaction between the glutamatergic and chloride transport systems highlights a novel homeostatic mechanism whereby ambient glutamate levels directly regulate the inhibitory synaptic tone by setting the activity level of KCC2. Chlorides 47-55 solute carrier family 12 member 5 Homo sapiens 228-232 18500393-6 2008 The neuronal chloride concentration is increased by Na+-K+-Cl(-)-Cl(-) cotransporters 1 (NKCC1), and decreased by K+-Cl(-) cotransporter 2 (KCC2). Chlorides 13-21 solute carrier family 12 member 5 Homo sapiens 114-138 18625303-1 2008 The neuron-specific potassium-chloride cotransporter 2 (KCC2) plays a crucial role, by controlling chloride extrusion, in the development and maintenance of inhibitory neurotransmission. Chlorides 30-38 solute carrier family 12 member 5 Homo sapiens 56-60 18524541-4 2008 The switch from depolarizing to hyperpolarizing GABA(A)-ergic signaling is triggered through the developmental shift in the balance of chloride cotransporters that either increase (i.e. NKCC1) or decrease (i.e. KCC2) intracellular chloride. Chlorides 135-143 solute carrier family 12 member 5 Homo sapiens 211-215 18596173-4 2008 Here, we show in lesioned CA3 hippocampal neurons in vitro and in axotomized corticospinal neurons in vivo that posttraumatic downregulation of the neuron-specific K-Cl cotransporter KCC2 leads to intracellular chloride accumulation by the Na-K-2Cl cotransporter NKCC1, resulting in GABA-induced [Ca2+](i) transients. Chlorides 211-219 solute carrier family 12 member 5 Homo sapiens 183-187 18769373-3 2008 These transporters include the Na-K-2Cl cotransporter NKCC1, which mediates chloride influx, and various K-Cl cotransporters--such as KCC2 and KCC3-that extrude chloride. Chlorides 161-169 solute carrier family 12 member 5 Homo sapiens 134-138 18769373-5 2008 Altered chloride homeostasis, resulting from mutation or dysfunction of NKCC1 and/or KCC2, causes neuronal hypoexcitability or hyperexcitability; such derangements have been implicated in the pathogenesis of seizures and neuropathic pain. Chlorides 8-16 solute carrier family 12 member 5 Homo sapiens 85-89 18500393-6 2008 The neuronal chloride concentration is increased by Na+-K+-Cl(-)-Cl(-) cotransporters 1 (NKCC1), and decreased by K+-Cl(-) cotransporter 2 (KCC2). Chlorides 13-21 solute carrier family 12 member 5 Homo sapiens 140-144 17693402-1 2007 The potassium chloride cotransporter KCC2 plays a major role in the maintenance of transmembrane chloride potential in mature neurons; thus KCC2 activity is critical for hyperpolarizing membrane currents generated upon the activation of gamma-aminobutyric acid type A and glycine (Gly) receptors that underlie fast synaptic inhibition in the adult central nervous system. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 37-41 17949820-7 2008 This post-synaptic action depends on the intracellular concentration of chloride ions ([Cl(-)](i)) which is regulated by a protein in the plasma membrane: the K(+)-Cl(-) cotransporter (KCC2) extruding both K(+) and Cl(-) ions. Chlorides 72-80 solute carrier family 12 member 5 Homo sapiens 159-189 17693402-1 2007 The potassium chloride cotransporter KCC2 plays a major role in the maintenance of transmembrane chloride potential in mature neurons; thus KCC2 activity is critical for hyperpolarizing membrane currents generated upon the activation of gamma-aminobutyric acid type A and glycine (Gly) receptors that underlie fast synaptic inhibition in the adult central nervous system. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 140-144 16905250-1 2006 The potassium-chloride cotransporter 2 (KCC2)-dependent intracellular chloride level determines whether neurons respond to GABA and/or glycine by depolarization or hyperpolarization. Chlorides 14-22 solute carrier family 12 member 5 Homo sapiens 40-44 17910576-3 2007 This functional switch has been attributed to age-related differences in the relative abundance of cation chloride cotransporters, such as KCC2 and NKCC1, which regulate chloride homeostasis. Chlorides 106-114 solute carrier family 12 member 5 Homo sapiens 139-143 17192429-1 2006 The expression of the neuron-specific K+/Cl- cotransporter (KCC2) is restricted to the CNS and is strongly upregulated during neuronal maturation, yielding a low intracellular chloride concentration that is required for fast synaptic inhibition in adult neurons. Chlorides 176-184 solute carrier family 12 member 5 Homo sapiens 60-64 16905250-2 2006 However, still unknown is the role of KCC2-dependent chloride homeostasis in regulating the spontaneous activity of neuronal circuits via GABA(A) receptor (GABA(A)R) and the glycine receptor (GlyR). Chlorides 53-61 solute carrier family 12 member 5 Homo sapiens 38-42 16905250-8 2006 Our findings suggest that KCC2-dependent chloride homeostasis is mainly involved in GABA(A)R-mediated synaptic inhibition whereas GlyR-mediated tonic action plays a totally different role in regulating hippocampal circuit activity. Chlorides 41-49 solute carrier family 12 member 5 Homo sapiens 26-30 15888655-3 2005 Here, we bring the first experimental evidence in vivo in the retina that chronic activation of GABA(A) receptors is necessary for the switch to occur and for the chloride extrusion mechanism (through the K+/Cl- cotransporter KCC2) to develop. Chlorides 163-171 solute carrier family 12 member 5 Homo sapiens 226-230 16291749-1 2006 The neuron-specific K(+)-Cl(-) cotransporter KCC2 plays a crucial role in determining intracellular chloride activity and thus the neuronal response to gamma-aminobutyric acid and glycine. Chlorides 100-108 solute carrier family 12 member 5 Homo sapiens 45-49 15888655-8 2005 Concomitantly, the developmental upregulation of KCC2 is inhibited on dendritic processes in the inner plexiform layer, suggesting that the intracellular concentration of chloride remains higher, as in younger cells. Chlorides 171-179 solute carrier family 12 member 5 Homo sapiens 49-53 14992262-3 2004 In particular, intracellular chloride activity and hence the neuronal response to GABA and glycine appears to be determined by a balance between chloride efflux and influx through KCC2 and the Na+-K+-2Cl- cotransporter NKCC1, respectively. Chlorides 29-37 solute carrier family 12 member 5 Homo sapiens 180-184 15140939-1 2004 GABA-mediated fast-hyperpolarizing inhibition depends on extrusion of chloride by the neuron-specific K-Cl cotransporter, KCC2. Chlorides 70-78 solute carrier family 12 member 5 Homo sapiens 122-126 34620512-1 2021 The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. Chlorides 90-98 solute carrier family 12 member 5 Homo sapiens 54-58 12930801-5 2003 Around hatching, waves gradually become stationary patches, whereas GABA(A) shifts from excitatory to inhibitory, coinciding with the upregulation of the cotransporter KCC2, suggesting that changes in intracellular chloride underlie the shift. Chlorides 215-223 solute carrier family 12 member 5 Homo sapiens 168-172 11027226-3 2000 To test this, we immunostained retina for the K-Cl cotransporter (KCC2) that normally extrudes chloride and for the Na-K-Cl cotransporter (NKCC) that normally accumulates chloride. Chlorides 95-103 solute carrier family 12 member 5 Homo sapiens 66-70 34883135-1 2022 The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl cotransporter KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation and consequent effects on GABAergic signaling have been implicated in numerous CNS disorders. Chlorides 149-157 solute carrier family 12 member 5 Homo sapiens 76-80 34955901-8 2021 In this review, we discuss the recent findings of the action of Shh-Smo signaling pathways on chloride ions homeostasis through the control of KCC2 membrane trafficking, and consequently on inhibitory neurotransmission and network activity during postnatal development. Chlorides 94-102 solute carrier family 12 member 5 Homo sapiens 143-147 35448033-2 2022 NKCC1, encoded by the SLC12A2 gene, regulates neuronal Cl- homeostasis by chloride import working opposite KCC2. Chlorides 74-82 solute carrier family 12 member 5 Homo sapiens 107-111 34849164-6 2021 The chloride (Cl-) levels in GABAergic neurons are controlled by two solute carrier 12 (SLC12) cation-chloride-cotransporters (CCCs): Na+/K+/Cl- co-transporter (NKCC1) and K+/Cl- co-transporter (KCC2), that respectively cause an influx and efflux of Cl-. Chlorides 4-12 solute carrier family 12 member 5 Homo sapiens 195-199 34858138-8 2021 However, there was a reduction in phosphorylated KCC2 at the membrane, suggesting an increase in KCC2 chloride export activity. Chlorides 102-110 solute carrier family 12 member 5 Homo sapiens 97-101 34707084-1 2021 Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. Chlorides 120-128 solute carrier family 12 member 5 Homo sapiens 169-173 34707084-1 2021 Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. Chlorides 246-254 solute carrier family 12 member 5 Homo sapiens 169-173 35159205-2 2022 The control of (Cl-)i levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. Chlorides 117-125 solute carrier family 12 member 5 Homo sapiens 82-86