Article
Cell Biology
Rebecca Jarvis, Shu Fun Josephine Ng, Anna J. Nathanson, Ross A. Cardarelli, Krithika Abiraman, Fergus Wade, Aidan Evans-Strong, Marina P. Fernandez-Campa, Tarek Z. Deeb, Joshua L. Smalley, Tanguy Jamier, Ian K. Gurrell, Lisa McWilliams, Aarti Kawatkar, Leslie C. Conway, Qi Wang, Roland W. Burli, Nicholas J. Brandon, Iain P. Chessell, Aaron J. Goldman, Jamie L. Maguire, Stephen J. Moss
Summary: Activation of KCC2 can reduce benzodiazepine-resistant seizures and decrease associated neuronal damage.
CELL REPORTS MEDICINE
(2023)
Article
Cell Biology
Egor Byvaltcev, Mahraz Behbood, Jan-Hendrik Schleimer, Thomas Gensch, Alexey Semyanov, Susanne Schreiber, Ulf Strauss
Summary: Extracellular potassium [K+]o elevation during synaptic activity retrogradely modifies presynaptic release and astrocytic uptake of glutamate. Hence, local K+ clearance and replenishment mechanisms are crucial regulators of glutamatergic transmission and plasticity. Based on recordings of astrocytic inward rectifier potassium current IKir and K+-sensitive electrodes as sensors of [K+]o as well as on in silico modeling, we demonstrate that the neuronal K+-Cl- co-transporter KCC2 clears local perisynaptic [K+]o during synaptic excitation by operating in an activity-dependent reversed mode.
Review
Neurosciences
Kelvin K. Hui, Thomas E. Chater, Yukiko Goda, Motomasa Tanaka
Summary: Excitatory-inhibitory (E-I) imbalance is a contributing factor to various neurodevelopmental disorders. Dysregulation of GABA neurotransmission and chloride homeostasis is associated with these abnormalities. Recent evidence suggests that the GABA-shift phenomenon may be involved in neuropsychiatric disorders. This review discusses the cell signaling and regulatory mechanisms underlying the GABA-shift, explores the interactions between GABAergic interneurons and other cell types, and outlines recent progress in targeting NKCC1 and KCC2 as a therapeutic strategy.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Neurosciences
Abhishek Pethe, Mira Hamze, Marina Giannaki, Bernd Heimrich, Igor Medina, Anna-Maria Hartmann, Eleni Roussa
Summary: This study investigates the effects of KCC2/NBCe1 interaction on the phosphorylation pattern and function of KCC2. The results show that KCC2 and NBCe1 interact in the mouse brain and this interaction may have pathophysiological relevance.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Neurosciences
Michele Yeo, Qiaojuan Zhang, LeAnne Ding, Xiangjun Shen, Yong Chen, Wolfgang Liedtke
Summary: Low intraneuronal chloride in spinal cord dorsal horn (SCDH) pain relay neurons is crucial for normal pain transmission, while high chloride levels can lead to pain hypersensitivity and allodynia. Recent findings show that kenpaullone can enhance Kcc2 gene expression, thereby repairing the diminished expression and function of KCC2 in SCDH neurons, and potentially providing therapeutic effects for chemotherapy-induced pain and chronic pruritus.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Georgina Kontou, Shu Fun Josephine Ng, Ross A. Cardarelli, Jack H. Howden, Catherine Choi, Qiu Ren, Miguel A. Rodriguez Santos, Christopher E. Bope, Jake S. Dengler, Matt R. Kelley, Paul A. Davies, Josef T. Kittler, Nicholas J. Brandon, Stephen J. Moss, Joshua L. Smalley
Summary: KCC2 plays a critical role in maintaining neuronal survival in mature neurons, while having minimal impact on neuronal development and structure. The loss of KCC2 function in mature neurons can rapidly activate the apoptotic pathway. In contrast, ablating KCC2 expression in immature neurons does not significantly affect their subsequent development.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Peripheral Vascular Disease
Richard A. Preston, David Afshartous, Evelyn Caizapanta, Barry J. Materson, Rolando Rodco, Eileen Alonso, Alberto B. Alonso
Summary: NCC activity did not significantly affect sodium sensitivity in metabolic syndrome hypertension, with 35 mmol KCl producing a rapid natriuresis approximately half that of 50 mg HCTZ and greater kaliuresis.
Article
Medicine, Research & Experimental
Issa Alhamoud, Susan K. Legan, Jyothsna Gattineni, Michel Baum
Summary: Prenatal dexamethasone has been shown to increase blood pressure in male offspring, resulting in proteinuria, but not in female offspring. The increase in blood pressure is possibly related to an increase in renal tubular transporter protein abundance, rather than changes in renin and aldosterone levels.
EXPERIMENTAL BIOLOGY AND MEDICINE
(2021)
Review
Chemistry, Multidisciplinary
Erin McMoneagle, Jin Zhou, Shiyao Zhang, Weixue Huang, Sunday Solomon Josiah, Ke Ding, Yun Wang, Jinwei Zhang
Summary: Epilepsy is a neurological disorder characterized by seizures, and impaired function of the KCC2 protein has been found to contribute to its pathogenesis. Enhancing KCC2 activation and regulating its phosphorylation and transcription have shown promising results in attenuating seizure severity. Recent advances in understanding the regulatory mechanisms of KCC2 have led to the discovery of novel small molecules that modulate its activity, making it a potential therapeutic target for treating epilepsy.
ACTA PHARMACOLOGICA SINICA
(2023)
Review
Endocrinology & Metabolism
Aihua Wu, Martin J. Wolley, Robert A. Fenton, Michael Stowasser
Summary: The thiazide-sensitive sodium chloride cotransporter (NCC) plays a major role in electrolyte balance and blood pressure regulation. The renal-K+ switch mechanism, which links dietary potassium intake to NCC activity, may offer new targets for blood pressure control. However, the lack of human data to confirm findings from animal models is a hurdle for full acceptance of this model. Urinary extracellular vesicles (uEVs) have potential as biomarkers for studying renal physiology and pathology. Challenges include the diverse origins and dynamic molecular composition of uEVs.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Clinical Neurology
Sissel Loseth, Helle Hoyer, Kim-Mai Le, Eric Delpire, Einar Kinge, Asgeir Lande, Hilde Tveitan Hilmarsen, Toril Fagerheim, Oivind Nilssen, Geir Julius Braathen
Summary: Loseth et al. describe a new and milder phenotype of hereditary neuropathy associated with a heterozygous mutation in the SLC12A6 gene, inherited over multiple generations. The phenotype in the affected families demonstrated heterogeneity, with some patients having subtle to moderate symptoms and even some individuals having no complaints. The functional characterization of the mutant potassium chloride cotransporter 3 revealed a significant reduction in potassium influx, expanding the spectrum of SLC12A6 disease.
Review
Pharmacology & Pharmacy
Shihan Salihu, Nur Farah Meor Azlan, Sunday Solomon Josiah, Zhijuan Wu, Yun Wang, Jinwei Zhang
Summary: The circadian system is controlled by the suprachiasmatic nucleus (SCN), and GABAergic neurons play a role in regulating the circadian rhythms by controlling chloride levels. Recent studies have shown excitatory responses in this area due to an increase in chloride ion levels. Changes in the expression and activity of the cation-chloride cotransporters NKCC1 and KCC2 in SCN neurons are associated with circadian rhythms.
ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Urology & Nephrology
Qi Wu, Soren B. Poulsen, Sathish K. Murali, Paul R. Grimm, Xiao-Tong Su, Eric Delpire, Paul A. Welling, David H. Ellison, Robert A. Fenton
Summary: This study utilized mass spectrometry to compare the correlations between protein levels in urinary extracellular vesicles (uEVs) and kidney tissue, finding a positive correlation between them; transmembrane proteins showed higher correlations than cytoplasmic proteins; the changes in various proteins had a monotonic relationship with alterations in the kidney after dietary K+ manipulation.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2021)
Article
Genetics & Heredity
Monis Bilal Shamsi, Mohamed Saleh, Makki Almuntashri, Essa Alharby, Manar Samman, Roy W. A. Peake, Fatima M. Al-Fadhli, Ali Alasmari, Eissa A. Faqeih, Naif A. M. Almontashiri
Summary: Heterozygous pathogenic variants in SLC12A2 have been linked to nonsyndromic hearing loss, while homozygous loss-of-function variants have been associated with syndromic intellectual disability. Variants in the c-terminal domain of the SLC12A2 gene seem to play a critical role in the functioning of the encoded co-transporter protein. The study provides additional confirmation of the autosomal recessive SLC12A2 disease.
JOURNAL OF HUMAN GENETICS
(2021)
Review
Pediatrics
Michiel L. A. J. Wieers, Jaap Mulder, Joris Rotmans, Ewout J. Hoorn
Summary: By controlling urinary potassium excretion, the kidneys play a key role in maintaining whole-body potassium homeostasis. Conversely, low urinary potassium excretion is recognized as a risk factor for the progression of kidney disease. There is a reciprocal relationship between potassium and the kidney, where the kidney regulates potassium balance and potassium also affects kidney function.
PEDIATRIC NEPHROLOGY
(2022)