Intracellular Chloride Regulation

Álvarez-Leefmans, Francisco J.

doi:10.1016/b978-0-12-387738-3.00015-9

Cited by 14 publications

(4 citation statements)

References 182 publications

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“…Electrochemical proton (H + ) gradients represent a ubiquitous source of energy in live cells. The chloride ion (Cl – ), the most abundant anion in organisms, controls pH within cell compartments by shunting the effects of H + charge accumulation on membrane potential. − The importance of Cl – in cell functions was not fully recognized until recently, yet Cl – and H + play coordinated roles in physiological processes including control of membrane potential, regulation of cell volume, , growth and migration of neurons, − and synaptic signaling in both the depolarizing and hyperpolarizing directions. , Intracellular Cl – concentration is tightly regulated by the interaction of energy-dependent transporters with passive-diffusion channels so that a gradient of varying intensity over time is established across the plasma membrane . Cl – homeostasis is of high significance in the physiopathology of many human diseases such as cystic fibrosis, myotonia, epilepsy, lysosomal storage diseases, and neurodevelopmental disorders including autism, fragile X syndrome, and Down syndrome .…”

mentioning

confidence: 99%

Synchronous Bioimaging of Intracellular pH and Chloride Based on LSS Fluorescent Protein

Paredes

Idilli²,

Mariotti

et al. 2016

ACS Chem. Biol.

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Ion homeostasis regulates critical physiological processes in the living cell. Intracellular chloride concentration not only contributes in setting the membrane potential of quiescent cells but it also plays a role in modulating the dynamic voltage changes during network activity. Dynamic chloride imaging demands new tools, allowing faster acquisition rates and correct accounting of concomitant pH changes. Joining a long-Stokes-shift red-fluorescent protein to a GFP variant with high sensitivity to pH and chloride, we obtained LSSmClopHensor, a genetically encoded fluorescent biosensor optimized for the simultaneous chloride and pH imaging and requiring only two excitation wavelengths (458 and 488 nm). LSSmClopHensor allowed us to monitor the dynamic changes of intracellular pH and chloride concentration during seizure like discharges in neocortical brain slices. Only cells with tightly controlled resting potential revealed a narrow distribution of chloride concentration peaking at about 5 and 8 mM, in neocortical neurons and SK-N-SH cells, respectively. We thus showed that LSSmClopHensor represents a new versatile tool for studying the dynamics of chloride and proton concentration in living systems.

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mentioning

confidence: 99%

Synchronous Bioimaging of Intracellular pH and Chloride Based on LSS Fluorescent Protein

Paredes

Idilli²,

Mariotti

et al. 2016

ACS Chem. Biol.

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“…(2003) in HEK‐293 cells) as a reference value. The K i /IC 50 of bumetanide for NKCC1 is often cited to be around 100–300 nM (Puskarjov et al., 2014), although the sensitivity of mammalian NKCC1 to bumetanide may vary over almost two orders of magnitude, depending on animal species, cell type, the activation state of NKCC1, and whether measurements are done in native/endogenous NKCC1 or heterologous expression systems (Alvarez‐Leefmans, 2012; Löscher & Kaila, 2022; Russell, 2000). For a selective block of NKCC1 by bumetanide, concentrations of 1–10 μM are often used (Blaesse et al., 2009; Russell, 2000), and 1 μM has been used as a cutoff for pharmacokinetic considerations in mouse studies (Brandt et al., 2018).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous brain distribution of bumetanide following systemic administration in rats

Löscher,

Gramer,

Römermann

2024

Biopharm & Drug Disp

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Bumetanide is used widely as a tool and off‐label treatment to inhibit the Na‐K‐2Cl cotransporter NKCC1 in the brain and thereby to normalize intra‐neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood–brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10 mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5‐fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC50 (2.4 μM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.

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“…The functional, pharmacological, regulatory, and kinetic properties of mKCC4 were carefully established by Mount et al [19] and Mercado et al [76] using heterologous expression in Xenopus laevis oocytes [ reviewed in [4]]. Interestingly, over-expression of mKCC4 resulted in robust K-Cl cotransport activity only under hypotonic conditions.…”

Section: Slc12a7 (Kcc4)mentioning

confidence: 99%

“…Together, these plasma membrane transport proteins represent the Na + -dependent cation-chloride cotransporter branches of the SLC12A family. Each of these cotransporters is involved in the electroneutral accumulation of CI - using the energy stored in the combined Na + , K + , and CI - chemical gradients [ reviewed in [4]]. An extensive in silico analysis of the potential splice variants of the Na + -dependent cation-chloride cotransporters ( SLC12A1-SLC12A3 ) was published recently [1].…”

Section: Introductionmentioning

confidence: 99%

A Molecular Analysis of the Na⁺-Independent Cation Chloride Cotransporters

Gagnon

Fulvio

2013

Cell Physiol Biochem

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The homologous genes encoding the electroneutral solute carrier family 12A (SLC12A) were identified more than 20 years ago, however, over the last few years, it has become clear that each of the genes within this family potentially encode for more than one cation-chloride cotransporter (CCC). Even more surprising, despite more than 30 years of functional studies and a wealth of knowledge on the activators, inhibitors, ion affinities, and kinetics of these cotransporters, we still cannot sufficiently explain why some cells express only one CCC isoform, while others express two, three, or more CCC isoforms. In 2009, Drs. Alvarez-Leefmans and Di Fulvio published an extensive in silico molecular analysis of the potential splice variants of the Na⁺-dependent cation-chloride cotransporters. In this review, we will look at the exceptionally large variety of potential splice variants within the Na⁺-independent cation-chloride cotransporter (SLC12A4-SLC12A7) genes, their initial tissue identification, and their physiological relevance.

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Intracellular Chloride Regulation

Cited by 14 publications

References 182 publications

Synchronous Bioimaging of Intracellular pH and Chloride Based on LSS Fluorescent Protein

Synchronous Bioimaging of Intracellular pH and Chloride Based on LSS Fluorescent Protein

Heterogeneous brain distribution of bumetanide following systemic administration in rats

A Molecular Analysis of the Na⁺-Independent Cation Chloride Cotransporters

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Intracellular Chloride Regulation

Cited by 14 publications

References 182 publications

Synchronous Bioimaging of Intracellular pH and Chloride Based on LSS Fluorescent Protein

Synchronous Bioimaging of Intracellular pH and Chloride Based on LSS Fluorescent Protein

Heterogeneous brain distribution of bumetanide following systemic administration in rats

A Molecular Analysis of the Na+-Independent Cation Chloride Cotransporters

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A Molecular Analysis of the Na⁺-Independent Cation Chloride Cotransporters