Author Correction: Cryo-EM structures of the full-length human KCC2 and KCC3 cation-chloride cotransporters.
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ABSTRACT:
SUBMITTER: Chi X
PROVIDER: S-EPMC8324789 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC8182806 | biostudies-literature
Project description:An amendment to this paper has been published and can be accessed via a link at the top of the paper.
| S-EPMC7265381 | biostudies-literature
Project description:Cation-coupled chloride cotransporters (CCCs) modulate the transport of sodium and/or potassium cations coupled with chloride anions across the cell membrane. CCCs thus help regulate intracellular ionic concentration and consequent cell volume homeostasis. This has been largely exploited in the past to develop diuretic drugs that act on CCCs expressed in the kidney. However, a growing wealth of evidence has demonstrated that CCCs are also critically involved in a great variety of other pathologies, motivating most recent drug discovery programs targeting CCCs. Here, we examine the structure-function relationship of CCCs. By linking recent high-resolution cryogenic electron microscopy (cryo-EM) data with older biochemical/functional studies on CCCs, we discuss the mechanistic insights and opportunities to design selective CCC modulators to treat diverse pathologies.
| S-EPMC8461084 | biostudies-literature
Project description:Electrical activity in neurons requires a seamless functional coupling between plasmalemmal ion channels and ion transporters. Although ion channels have been studied intensively for several decades, research on ion transporters is in its infancy. In recent years, it has become evident that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K(+)-Cl(-) cotransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity. Studying the functions of these transporters may lead to major paradigm shifts in our understanding of the mechanisms underlying brain development and plasticity in health and disease.
| S-EPMC4294553 | biostudies-literature
Project description:Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children and adults. The paucity of evidence-based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in γ-aminobutyric acid (GABA)ergic neurotransmission between the immature and mature brain, and trauma-induced alterations in the function of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCCs are attractive drug targets, bumetanide and other existing CCC inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform-specific NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2-mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
| S-EPMC4284054 | biostudies-literature
Project description:The SLC12 family of cation-chloride-cotransporters (CCCs) is comprised of potassium chloride cotransporters (KCCs), which mediate Cl- extrusion and sodium-potassium chloride cotransporters (N[K]CCs), which mediate Cl- loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. The functions of CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells in addition to their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promotes the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings suggest hypothalamic signaling as a key signaling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.
| S-EPMC7602155 | biostudies-literature
Project description:Genomes of unicellular and multicellular green algae, mosses, grasses and dicots harbor genes encoding cation-chloride cotransporters (CCC). CCC proteins from the plant kingdom have been comparatively less well investigated than their animal counterparts, but proteins from both plants and animals have been shown to mediate ion fluxes, and are involved in regulation of osmotic processes. In this review, we show that CCC proteins from plants form two distinct phylogenetic clades (CCC1 and CCC2). Some lycophytes and bryophytes possess members from each clade, most land plants only have members of the CCC1 clade, and green algae possess only the CCC2 clade. It is currently unknown whether CCC1 and CCC2 proteins have similar or distinct functions, however they are both more closely related to animal KCC proteins compared to NKCCs. Existing heterologous expression systems that have been used to functionally characterize plant CCC proteins, namely yeast and Xenopus laevis oocytes, have limitations that are discussed. Studies from plants exposed to chemical inhibitors of animal CCC protein function are reviewed for their potential to discern CCC function in planta. Thus far, mutations in plant CCC genes have been evaluated only in two species of angiosperms, and such mutations cause a diverse array of phenotypes-seemingly more than could simply be explained by localized disruption of ion transport alone. We evaluate the putative roles of plant CCC proteins and suggest areas for future investigation.
| S-EPMC5855714 | biostudies-literature
Project description:The circadian system plays an immense role in controlling physiological processes in our body. The suprachiasmatic nucleus (SCN) supervises this system, regulating and harmonising the circadian rhythms in our body. Most neurons present in the SCN are GABAergic neurons. Although GABA is considered the main inhibitory neurotransmitter of the CNS, recent studies have shown that excitatory responses were recorded in this area. These responses are enabled by an increase in intracellular chloride ions [Cl-]i levels. The chloride (Cl-) levels in GABAergic neurons are controlled by two solute carrier 12 (SLC12) cation-chloride-cotransporters (CCCs): Na+/K+/Cl- co-transporter (NKCC1) and K+/Cl- co-transporter (KCC2), that respectively cause an influx and efflux of Cl-. Recent works have found altered expression and/or activity of either of these co-transporters in SCN neurons and have been associated with circadian rhythms. In this review, we summarize and discuss the role of CCCs in circadian rhythms, and highlight these recent advances which attest to CCC's growing potential as strong research and therapeutic targets.
| S-EPMC8609385 | biostudies-literature
Project description:The importance of the GABAergic system in spinal nociceptive processing has long been appreciated but we have only recently begun to understand how this system is modulated by the regulation of anion gradients. In neuronal tissues, cation-chloride cotransporters regulate Cl- homeostasis and the activity and/or expression of these transporters has important implications for the direction and magnitude of anion flow through GABA-A channels. Here we review recent evidence that two cation-chloride cotransporters, NKCC1 and KCC2 are involved in pain and enhanced nociception. On the one hand, NKCC1 activity is upregulated in primary afferents following an inflammatory insult and this produces excessive GABAergic depolarization in primary afferents leading to cross excitation between low and high threshold afferents. On the other hand, KCC2 expression is reduced in dorsal horn neurons following peripheral nerve injury resulting in a loss of GABA-/glycinergic inhibitory tone and, in some cases, inverting its action into net excitation. Pharmacological targeting of these cation chloride cotransporters to restore normal GABA-/glycinergic transmission in the spinal cord represents an entirely novel approach to the development of analgesics.
| S-EPMC1472095 | biostudies-literature
Project description:Cation chloride cotransporters (CCC) play an essential role for neuronal chloride homeostasis. K(+)-Cl(-) cotransporter (KCC2), is the principal Cl(-)-extruder, whereas Na(+)-K(+)-Cl(-) cotransporter (NKCC1), is the major Cl(-)-uptake mechanism in many neurons. As a consequence, the action of the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine strongly depend on the activity of these two transporters. Knowledge of the mechanisms involved in ion transport and regulation is thus of great importance to better understand normal and disturbed brain function. Although no overall 3-dimensional crystal structures are yet available, recent molecular and phylogenetic studies and modeling have provided new and exciting insights into structure-function relationships of CCC. Here, we will summarize our current knowledge of the gross structural organization of the proteins, their functional domains, ion binding and translocation sites, and the established role of individual amino acids (aa). A major focus will be laid on the delineation of shared and distinct organizational principles between KCC2 and NKCC1. Exploiting the richness of recently generated genome data across the tree of life, we will also explore the molecular evolution of these features.
| S-EPMC4301019 | biostudies-literature