The growing interest in the role of microglia in the progression of many neurodegenerative diseases is developing in an ever-expedited manner, in part thanks to emergent new tools for studying the morphological and functional features of the CNS. The discovery of specific biomarkers of the microglia phenotype could find application in a wide range of human diseases, and creates opportunities for the discovery and development of tailored therapeutic interventions. Among these, recent studies highlight the pivotal role of the potassium channels in regulating microglial functions in physiological and pathological conditions such as Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. In this review, we summarize the current knowledge of the involvement of the microglial potassium channels in several neurodegenerative diseases and their role as modulators of microglial homeostasis and dysfunction in CNS disorders.
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http://dx.doi.org/10.3390/biom11121774 | DOI Listing |
J Clin Hypertens (Greenwich)
January 2025
Department of Cardiology, Hypertension Research Laboratory, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Limited research has investigated the impact of antihypertensive medications on type 2 diabetes mellitus (T2DM) and whether gut microbiome (GM) mediates this association. Thus, we conducted a two-sample Mendelian randomization (MR) analysis to estimate the potential impact of various antihypertensive drug target genes on T2DM and its complications. Genetic instruments for the expression of antihypertensive drug target genes were identified with expression quantitative trait loci (eQTL) in blood, which should be associated with systolic blood pressure (SBP).
View Article and Find Full Text PDFJ Cereb Blood Flow Metab
January 2025
Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, USA.
Regional blood flow within the brain is tightly coupled to regional neuronal activity, a process known as neurovascular coupling (NVC). In this study, we demonstrate the striking role of SUR2- and Kir6.1-dependent ATP-sensitive potassium (K) channels in control of NVC in the sensory cortex of conscious mice, in response to mechanical stimuli.
View Article and Find Full Text PDFMalar J
January 2025
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Background: Emodepside is an anthelmintic used in veterinary medicine that is currently under investigation in human clinical trials for the treatment of soil-transmitted helminths and possibly Onchocerca volvulus. Emodepside targets the calcium-activated voltage-gated potassium slowpoke 1 (SLO-1) channels of presynaptic nerves of pharynx and body wall muscle cells of nematodes leading to paralysis, reduced locomotion and egg laying, starvation, and death. Emodepside also has activity against Drosophila melanogaster SLO-1 channels.
View Article and Find Full Text PDFNat Chem Biol
January 2025
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel.
View Article and Find Full Text PDFBr J Pharmacol
January 2025
Department of Physiology and Pharmacology, School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Background And Purpose: The antiepileptic drug ethosuximide (ETX) suppresses epileptiform activity in a mouse model of GNB1 syndrome, caused by mutations in Gβ protein, likely through the inhibition of G-protein gated K (GIRK) channels. Here, we investigated the mechanism of ETX inhibition (block) of different GIRKs.
Experimental Approach: We studied ETX inhibition of GIRK channels expressed in Xenopus oocytes with or without their physiological activator, the G protein subunit dimer Gβγ.
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