Multiple Roles of KCC2 in the Developing Brain

Uvarov, Pavel; Llano, Olaya; Ludwig, Anastasia; Airaksinen, Matti S.; Rivera, Claudio

doi:10.1016/b978-0-12-397266-8.00190-3

Cited by 4 publications

(2 citation statements)

References 159 publications

(182 reference statements)

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“…Despite being a potent NKCC1 antagonist, BTN can also antagonize KCC2 at higher concentrations (Delpire et al, 2009). The developmental upregulation of KCC2 has been elucidated and confirmed with a wide span of experimental techniques (Uvarov et al, 2013; Sedmak et al, 2016). The expression profile of KCC2 correlates with maturation of different brain regions (Watanabe and Fukuda, 2015; Côme et al, 2019).…”

Section: Maintaining the Transmembrane Cl− Gradientmentioning

confidence: 85%

Off-Label Use of Bumetanide for Brain Disorders: An Overview

2019

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Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl − gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl − importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl − levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.

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Section: Maintaining the Transmembrane Cl− Gradientmentioning

confidence: 85%

Off-Label Use of Bumetanide for Brain Disorders: An Overview

2019

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“…KCC2 is heavily expressed in the mature CNS and is rarely found in peripheral neurons and nonneuronal cells [46–48]. Upregulation of KCC2 is correlated with neuronal differentiation which occurs caudally to rostrally in the CNS [49].…”

Section: Neuronal Expression Of Kcc2mentioning

confidence: 99%

Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K⁺-Cl^-Cotransporter KCC2

Tillman

Zhang

2019

BioMed Research International

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Chloride (Cl-) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl- interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl- permeable GABAA receptor channels (GABAAR). This process is reliant on Cl- extruder K+-Cl- cotransporter 2 (KCC2), which generates the neuron’s inward, hyperpolarising Cl- gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family (SLC12A5) and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of SLC12A5 that negatively regulates the transporter’s expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2’s potential as a therapeutic target.

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Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain

Sedmak¹,

Jovanov-Milošević²,

Puskarjov

et al. 2015

Cereb. Cortex

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Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.

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Multiple Roles of KCC2 in the Developing Brain

Cited by 4 publications

References 159 publications

Off-Label Use of Bumetanide for Brain Disorders: An Overview

Off-Label Use of Bumetanide for Brain Disorders: An Overview

Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K⁺-Cl^-Cotransporter KCC2

Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain

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Multiple Roles of KCC2 in the Developing Brain

Cited by 4 publications

References 159 publications

Off-Label Use of Bumetanide for Brain Disorders: An Overview

Off-Label Use of Bumetanide for Brain Disorders: An Overview

Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K+-Cl-Cotransporter KCC2

Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain

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Product

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Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K⁺-Cl^-Cotransporter KCC2