Cl<sup>−</sup> as a bona fide signaling ion

Lüscher, Benjamin P.; Vachel, Laura; Ohana, Ehud; Muallem, Shmuel

doi:10.1152/ajpcell.00354.2019

Cited by 52 publications

(36 citation statements)

References 120 publications

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“…In developing neurons, NKCC1 major sites for (de)phosphorylation include two C-terminal threonines (T906 and T1007; Box 3). These residues are targeted by kinases of the WNK (With-No-Lysine) family, which act as sensors of [Cl − ] i [54]. WNK kinases are unique in that Cl − inhibits their autophosphorylation and consequent kinase activation [54].…”

Section: Regulation Of Kcc2 (De)phosphorylationmentioning

confidence: 99%

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The Multifaceted Roles of KCC2 in Cortical Development

Virtanen

Uvarov

Mavrović

et al. 2021

Trends in Neurosciences

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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). We describe the molecular and cellular mechanisms involved in the multiple functions of KCC2 and its splice variants, ranging from developmental apoptosis and the control of early network events to the formation and plasticity of cortical dendritic spines. The versatility of KCC2 actions at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease, and aging. Thus, KCC2 has emerged as one of the most important molecules that shape the overall neuronal phenotype. KCC2 in the Fundamental Machinery Underlying Neuronal Development, Signaling, and StructureFast synaptic transmission relies on ion fluxes through ligand-gated ion channels. Although the default state of a cell is to have a high intracellular chloride concentration ([Cl − ] i ), mature neurons in the CNS have evolved a unique ability to maintain a low [Cl − ] i , which is needed for the generation of hyperpolarizing Cl − currents across GABA A and glycine receptors (GABA A Rs and GlyRs) [1]. This specialization comes at a high energy cost [2], and is brought about by upregulation of the neuron-specific K-Cl cotransporter KCC2 during neuronal maturation [1,3,4]. KCC2 belongs to the evolutionarily ancient family of SLC12 cation/chloride cotransporters (CCCs) (Box 1; for KCCs and NKCCs, see Glossary) that have their roots in a single gene in Archaea, from which numerous duplication events in both archaeans and eukaryotes have led to the divergence and neofunctionalization of the paralogous CCC subfamilies [5]. Possibly because of a primordial role in cellular volume regulation, CCCs have evolved to communicate with the actin cytoskeleton. Indeed, KCC2 has emerged as an important player in controlling actin dynamics during neuronal development and plasticity [6][7][8][9].The functional upregulation of KCC2-mediated K-Cl cotransport in hippocampal and neocortical neurons underlies the hyperpolarizing shift in GABAergic currents which takes place postnatally in rats and mice [3], but it has become clear that KCC2 is expressed at low but functionally significant levels pre-and perinatally. KCC2 acts in an ion transport-independent manner as an antiapoptotic factor in projection neurons in the prenatal mouse neocortex [10]; in the perinatal mouse and rat hippocampus transport-functional KCC2 decreases the depolarizing driving force of GABA A R-mediated currents (DF GABA ), thereby influencing spontaneous network events at their developmental onset [11].In this review we highlight the developmental paths from KCC2 protein expression to its multiple functions, and discuss the wide variety of post-translational mechanisms which control these phenomena. The versatility of KCC2 regulation at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease,...

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Section: Regulation Of Kcc2 (De)phosphorylationmentioning

confidence: 99%

“…These residues are targeted by kinases of the WNK (With-No-Lysine) family, which act as sensors of [Cl − ] i [54]. WNK kinases are unique in that Cl − inhibits their autophosphorylation and consequent kinase activation [54]. Mature neurons express mainly WNK1 and, to a lesser extent, WNK3 [55].…”

Section: Regulation Of Kcc2 (De)phosphorylationmentioning

confidence: 99%

The Multifaceted Roles of KCC2 in Cortical Development

Virtanen

Uvarov

Mavrović

et al. 2021

Trends in Neurosciences

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“…The electrochemical gradient built across the plasma membrane is maintained primarily by the . Cl − [in] modulates the activity of transcription factors, protein kinases, and other ion transporters (Lüscher et al 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Upon cell stimulation, the gradient is rapidly altered together with Cl − [in] . Cl − [in] modulates the activity of transcription factors, protein kinases, and other ion transporters (Lüscher et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical physiology aspects of chloremia in fluid therapy: a systematic review

et al. 2020

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Background This systematic review discusses a clinical physiology aspect of chloride in fluid therapy. Crystalloid solutions are one of the most widely used remedies. While generally used in medicine for almost 190 years, studies focused largely on their safety have only been published since the new millennium. The most widely used solution, normal saline, is most often referred to in this context. Its excessive administration results in hyperchloremic metabolic acidosis with other consequences, including higher mortality rates. Methods Original papers and review articles eligible for developing the present paper were identified by searching online in the electronic MEDLINE database. The keywords searched for included hyperchloremia, hypochloremia, and compound words containing the word “chloride,” infusion therapy, metabolic acidosis, renal failure, and review. Results A total of 21,758 papers published before 31 May 2020 were identified; of this number, 630 duplicates were removed from the list. Upon excluding articles based on their title or abstract, 1850 papers were screened, of which 63 full-text articles were assessed. Conclusions According to the latest medical concepts, dyschloremia (both hyperchloremia and hypochloremia) represents a factor indisputably having a negative effect on selected variables of clinical outcome. As infusion therapy can significantly impact chloride homeostasis of the body, the choice of infusion solutions should always take into account the potentially adverse impact of chloride content on chloremia and organ function.

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“…The Concentration of Cl − is responsible for regulating cellular functions to maintain fluid and electrolyte homeostasis through multiple transporters [65] such as CLC transporter [66], CBE [67], and CFTR [20,40]. The concentration of extracellular Cl − controls the body fluid content of ions, cellular volume, and blood pressure [68].…”

Section: − As a Signaling Ionmentioning

confidence: 99%

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

Lee¹,

Hong²

2020

IJMS

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The bicarbonate ion has a fundamental role in vital systems. Impaired bicarbonate transport leads to various diseases, including immune disorders, cystic fibrosis, tumorigenesis, kidney diseases, brain dysfunction, tooth fracture, ischemic reperfusion injury, hypertension, impaired reproductive system, and systemic acidosis. Carbonic anhydrases are involved in the mechanism of bicarbonate movement and consist of complex of bicarbonate transport systems including bicarbonate transporters. This review focused on the convergent regulation of ion homeostasis through various ion transporters including bicarbonate transporters, their regulatory enzymes, such as carbonic anhydrases, pH regulatory role, and the expression pattern of ion transporters in non-secretory systems throughout the body. Understanding the correlation between these systems will be helpful in order to obtain new insights and design potential therapeutic strategies for the treatment of pH-related disorders. In this review, we have discussed the broad prospects and challenges that remain in elucidation of bicarbonate-transport-related biological and developmental systems.

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Cl⁻ as a bona fide signaling ion

Cited by 52 publications

References 120 publications

The Multifaceted Roles of KCC2 in Cortical Development

The Multifaceted Roles of KCC2 in Cortical Development

Clinical physiology aspects of chloremia in fluid therapy: a systematic review

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

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Cl− as a bona fide signaling ion

Cited by 52 publications

References 120 publications

The Multifaceted Roles of KCC2 in Cortical Development

The Multifaceted Roles of KCC2 in Cortical Development

Clinical physiology aspects of chloremia in fluid therapy: a systematic review

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

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Cl⁻ as a bona fide signaling ion