Roles of the cation–chloride cotransporters in neurological disease

Kahle, Kristopher T.; Staley, Kevin J.; Nahed, Brian V.; Gamba, Gerardo; Hebert, Steven C.; Lifton, Richard P.; Mount, David B.

doi:10.1038/ncpneuro0883

Cited by 356 publications

(348 citation statements)

References 113 publications

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“…Bumetanide inhibits the neuronal chloride cotransporter NKCC1, which acts as a chloride importer. Gamma-aminobutyric acid-mediated excitation has been observed when expression of NKCC1 is higher than expression of the chloride exporter KCC2; e.g., early during development and in the hippocampus of adults with temporal lobe epilepsy [58,59]. Based on the hypothesis that increased expression of NKCC1 may be involved in the development of neuronal hyperexcitability during epileptogenesis in adults, we evaluated whether treatment with bumetanide after pilocarpine-induced SE alters the long-term consequences of the brain insult [60].…”

Section: Examples For Synergistic Drug Combinationsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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Section: Examples For Synergistic Drug Combinationsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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“…Sodium inside the endothelial cell is then expelled into the brain's extracellular space by the activity of the Na + -K + -ATPase, with chloride and water following through chloride channels and unidentified water channels, respectively. Under physiological conditions, the activity of NKCC1 modulates the level of [Cl − ] i in neurons, glia, endothelial cells, and choroid plexus epithelial cells, thereby helping to maintain proper cellular volume against changes in extracellular osmolality and intracellular solute content [53]. Brain-injured states associated with ischemia have been demonstrated to cause upregulation of the transporter.…”

Section: Nkcc1mentioning

confidence: 99%

Novel Treatment Targets for Cerebral Edema

2012

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Cerebral edema is a common finding in a variety of neurological conditions, including ischemic stroke, traumatic brain injury, ruptured cerebral aneurysm, and neoplasia. With the possible exception of neoplasia, most pathological processes leading to edema seem to share similar molecular mechanisms of edema formation. Challenges to brain-cell volume homeostasis can have dramatic consequences, given the fixed volume of the rigid skull and the effect of swelling on secondary neuronal injury. With even small changes in cellular and extracellular volume, cerebral edema can compromise regional or global cerebral blood flow and metabolism or result in compression of vital brain structures. Osmotherapy has been the mainstay of pharmacologic therapy and is typically administered as part of an escalating medical treatment algorithm that can include corticosteroids, diuretics, and pharmacological cerebral metabolic suppression. Novel treatment targets for cerebral edema include the Na(+)-K(+)-2Cl(−) co-transporter (NKCC1) and the SUR1-regulated NC Ca-ATP (SUR1/TRPM4) channel. These two ion channels have been demonstrated to be critical mediators of edema formation in brain-injured states. Their specific inhibitors, bumetanide and glibenclamide, respectively, are well-characterized Food and Drug Administration-approved drugs with excellent safety profiles. Directed inhibition of these ion transporters has the potential to reduce the development of cerebral edema and is currently being investigated in human clinical trials. Another class of treatment agents for cerebral edema is vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A-and V2-receptor, conivaptan, promotes water excretion while sparing electrolytes through a process known as aquaresis.Keywords Cerebral edema . Hyponatraemia . Osmotherapy . NKCC1 . SUR1/TRPM4 . Vaptan . Glyburide Overview of Perturbations in Brain Fluid HomeostasisCerebral edema in the neurointensive care setting can occur with a heterogenous group of neurological diseases, which typically fall under the categories of metabolic [1, 2], infectious [3], neoplastic [4], cerebrovascular [5][6][7], and traumatic [8,9] brain injury. Irrespective of the inciting process, cerebral edema results in the pathological accumulation of fluid in the brain's intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between 4 distinct fluid compartments within the cranium; fluid is present within: 1) the blood in the cerebral blood vessels, 2) the cerebrospinal fluid in the ventricular system and subarachnoid space, 3) the interstitial fluid of the brain parenchyma, and 4) the intracellular fluid of the neurons and glia. These fluid compartments are not isolated, and specific movements of solutes and water from one compartment to another occur under normal conditions. When dysregulation of this normally tightly controlled fluid balance...

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“…In this way, the cell increases chloride entry along with water. Given that the long-term activity of SLC12 cotransporters changes the intracellular chloride concentration [Cl Ϫ ] i , the coordinated function of these cotransporters is also important for essential neurological functions because the way that postsynaptic cells respond to neurotransmitters that act on chloride channel-coupled receptors, such as ␥-aminobutyric acid (GABA), is defined by [Cl Ϫ ] i (11). Finally, the activity of the SLC12 cotransporters is also important to the regulation of transcellular ion transport in many epithelial cells, including the nephron, and thus is critical for blood pressure control (4).…”

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confidence: 99%

Similar effects of all WNK3 variants on SLC12 cotransporters

Cruz-Rangel

Melo

Vázquez

et al. 2011

American Journal of Physiology-Cell Physiology

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kinase 3 (WNK3) is a member of a subfamily of serine/threonine kinases that modulate the activity of the electroneutral cation-coupled chloride cotransporters. WNK3 activates NKCC1/2 and NCC and inhibits the KCCs. Four splice variants are generated from the WNK3 gene. Our previous studies focused on the WNK3-18a variant. However, it has been suggested that other variants could have different effects on the cotransporters. Thus, the present study was designed to define the effects of all WNK3 variants on members of the SLC12 family. By RT-PCR from a fetal brain library, exons 18b and 22 were separately amplified and subcloned into the original WNK3-18a or catalytically inactive WNK3-D294A to obtain all four potential combinations with and without catalytic activity (18a, 18aϩ22, 18b, and 18bϩ22). The basal activity of the cotransporters and the effects of WNK3 isoforms were assessed in Xenopus laevis oocytes coinjected with each of the WNK3 variant cRNAs. In isotonic conditions, the basal activity of NCC and NKCC1/2 were increased by coinjection with any of the WNK3. The positive effects occurred even in hypotonic conditions, in which the basal activity of NKCC1 is completely prevented. Consistent with these observations, when expressed in hypotonicity, all KCCs were active, but in the presence of any of the WNK3 variants, KCC activity was completely reduced. That is, NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. We conclude that the effects of all WNK3 variants toward SLC12 proteins are similar.

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Roles of the cation–chloride cotransporters in neurological disease

Cited by 356 publications

References 113 publications

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Novel Treatment Targets for Cerebral Edema

Similar effects of all WNK3 variants on SLC12 cotransporters

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