The signaling role for chloride in the bidirectional communication between neurons and astrocytes

Wilson, Corinne S.; Mongin, Alexander A.

doi:10.1016/j.neulet.2018.01.012

Cited by 52 publications

(45 citation statements)

References 220 publications

(169 reference statements)

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“…Finally, changes in Cl − concentration ([Cl − ] i ), induced by activation of Cl − ‐dependent transporters and/or Cl − channels are linked to activity‐related changes in the cellular volume of astrocytes (Chen & Sun, ; Kimelberg et al . ; Wilson & Mongin, ). The properties and functional role of Ca 2+ signalling has been extensively reviewed in the past, and in this paper we shall therefore focus on the signalling role of the other four major monovalent ions: Na + , Cl − , K + and H + .…”

Section: Ionic Signallingmentioning

confidence: 99%

“…It has been shown that this directly facilitates their migration and infiltration in dense tissue (Ransom et al . ); (iii) modulation of several types of ion channels such as K + channels and TRPM7 channels through direct binding to yet uncharacterised channel protein domains; and (iv) regulation of intracellular signalling cascades such as WNK (With No lysine [K + ]) and serine/threonine protein kinases (see Wilson & Mongin, for details and relevant literature). At the same time astroglial [Cl − ] i may play an important role in maintenance and regulation of inhibitory transmission in the CNS.…”

Section: Astroglial Cl− – the Link To Cell Biology And Regulator Of Imentioning

confidence: 99%

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Ionic signalling in astroglia beyond calcium

Verkhratsky

Untiet

Rose

2019

The Journal of Physiology

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Alexei Verkhratsky is an internationally recognised scholar in the field of cellular neurophysiology. His research is concentrated on the mechanisms of inter-and intracellular signalling in the CNS, being especially focused on two main types of neural cells, on neurones and neuroglia. He made important contributions to understanding chemical and electrical transmission in reciprocal neuronal-glial communications and the role of intracellular Ca 2+ signals in integrative processes in the nervous system. Many of his studies are dedicated to investigations of cellular mechanisms of neurodegeneration. He was the first to perform intracellular Ca 2+ recordings in old neurones in isolation and in situ, which provided direct experimental support for the 'Ca 2+ hypothesis of neuronal ageing' . In recent years he has studied glial ageing and gliopathology in age-related brain diseases, including Alzheimer's disease and neuropsychiatric diseases. He authored a pioneering hypothesis of astroglial atrophy as a general mechanism of cognitive brain disorders including neurodegenerative and psychiatric diseases. He was among 30 most-cited European neuroscientists in 2016.

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Section: Ionic Signallingmentioning

confidence: 99%

Section: Astroglial Cl− – the Link To Cell Biology And Regulator Of Imentioning

confidence: 99%

Ionic signalling in astroglia beyond calcium

Verkhratsky

Untiet

Rose

2019

The Journal of Physiology

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“…12.1A). The low intracellular [Cl − ] compensates for the presence of the net-negatively charged macromolecules (e.g., proteins and polynucleotides) and numerous organic metabolites [see discussion in (Lang et al, 1998; Hoffmann et al, 2009) and the “neurocentric” view in (Wilson & Mongin, 2019)].…”

Section: Common and Unique Aspects Of Osmotic Balance Within The Cnsmentioning

confidence: 99%

“…The “classical” KCC1, KCC3, and KCC4 are silent under basal conditions but are activated by increases in cell volume, while the neuron-specific KCC2 is basally active and additionally stimulated by cell swelling (Lauf & Adragna, 2000; Gamba, 2005). The contribution of KCCs to neuronal cell volume control has been suggested in the past but never definitively tested (Kahle et al, 2015; Wilson & Mongin, 2019). In one study, cultured hippocampal pyramidal neurons from KCC3-null mice showed a lack of RVD in hypoosmotic media (Boettger et al, 2003).…”

Section: Rvd In the Cns Cellsmentioning

confidence: 99%

Cell Volume Control in Healthy Brain and Neuropathologies

Wilson

Mongin

2018

Cell Volume Regulation

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Regulation of cellular volume is a critical homeostatic process that is intimately linked to ionic and osmotic balance in the brain tissue. Because the brain is encased in the rigid skull and has a very complex cellular architecture, even minute changes in the volume of extracellular and intracellular compartments have a very strong impact on tissue excitability and function. The failure of cell volume control is a major feature of several neuropathologies, such as hyponatremia, stroke, epilepsy, hyperammonemia, and others. There is strong evidence that such dysregulation, especially uncontrolled cell swelling, plays a major role in adverse pathological outcomes. To protect themselves, brain cells utilize a variety of mechanisms to maintain their optimal volume, primarily by releasing or taking in ions and small organic molecules through diverse volume-sensitive ion channels and transporters. In principle, the mechanisms of cell volume regulation are not unique to the brain and share many commonalities with other tissues. However, because ions and some organic osmolytes (e.g., major amino acid neurotransmitters) have a strong impact on neuronal excitability, cell volume regulation in the brain is a surprisingly treacherous process, which may cause more harm than good. This topical review covers the established and emerging information in this rapidly developing area of physiology.

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“…The inattention to Clmay be traced back to the pioneering work on neuronal action potentials by Hodgkin and Huxley, who characterized Clas responsible for only minor "leak" currents 1 . While it is now recognized that Clmovement is critical for homeostatic functions in the brain, including regulation of cell volume and pH [2][3][4][5][6] , the role of Clin excitability remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a potent and specific inhibitor for the CLC-2 chloride channel

Bois

Maduke

Huguenard

2020

Preprint

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CLC-2 is a voltage-gated chloride channel expressed ubiquitously in mammalian tissue. Studies to define how CLC-2 contributes to normal and pathophysiological brain function have produced controversial results, in part due to the absence of precise pharmacological tools for modulating CLC-2 function. Herein, we describe the development and optimization of a new small-molecule inhibitor of CLC-2, AK-42, that exhibits unprecedented potency and specificity. Computational docking, validated by mutagenesis and kinetic studies, indicates that AK-42 binds to an extracellular vestibule above the channel pore. AK-42 acutely and specifically inhibits CLC-2 currents in CA1 hippocampal pyramidal neurons. Use of AK-42 in an established thalamic-slice model for studying epilepsy suggests a role for CLC-2 in modulating electrical excitability and implicates CLC-2 as a possible anti-epileptic target. These results establish AK-42 as a powerful new tool for investigating CLC-2 physiology in the central nervous system.The CLC-2 channel belongs to the "CLC" family of Cl --selective ion channels and transporters, of which there are nine mammalian homologs 9 . CLC-2 is activated by hyperpolarization of the plasma membrane and is expressed in nearly every tissue-type, including brain, heart, intestines, and lungs 10 . Interest in CLC-2 physiology in the CNS was sparked by CLC-2 knockout mouse phenotypes, which display severe deficiencies, including retinal degeneration/blindness and vacuolization of myelin in brain tissue [11][12][13] . In addition, human patient data suggest a link between CLC-2 malfunction and certain forms of generalized epilepsies [14][15][16][17][18][19][20][21] . Although a causative role for CLC-2 underlying genetic disease remains controversial 22,23 , the available research, together with the widespread expression of CLC-2 in the CNS 10,11,24-28 , motivate further examination of this channel.Understanding CLC-2 physiology has proven difficult in the absence of selective and specific chemical reagents for labeling and modulating the activity of this ion channel. Commercially available Cl --channel inhibitors 29 lack potency, with mid-µM to mM concentrations required to achieve inhibition of Clcurrent 9,30-32 .These molecules also generally lack selectivity against the different types of Clchannels, which strictly limits the usefulness of these compounds for cellular and organismal studies. For the CLC channels, the most potent and selective small-molecule inhibitors are those targeting CLC-Ka, one of two CLC homologs expressed in the kidney [33][34][35][36] . For CLC-2, the only reported small-molecule (non-peptide) inhibitors require application of high concentrations (~1 mM) 9,10,24,37 . CLC-2 is also inhibited by low µM concentrations of the divalent cations, Cd 2+ and Zn 2+ 38,39 ; however, these ions are toxic and lack subtype specificity. A peptide toxin, GaTx2, has been reported to selectively inhibit CLC-2 at concentrations of ~20 pM 40 ; however, current inhibition saturates at ~50% with the applicat...

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The signaling role for chloride in the bidirectional communication between neurons and astrocytes

Cited by 52 publications

References 220 publications

Ionic signalling in astroglia beyond calcium

Ionic signalling in astroglia beyond calcium

Cell Volume Control in Healthy Brain and Neuropathologies

Development and validation of a potent and specific inhibitor for the CLC-2 chloride channel

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