The existence in mitochondria of separate, highly regulated pathways for K+ influx and efflux strongly implies that mitochondrial volume is subject to regulation in vivo. Volume, in turn has been shown to regulate activity of the electron transport chain. Thus, the mitochondrial K+ cycle appears to play a key signalling role in regulating cellular bioenergetics, including the metabolic fate of fatty acids. Consistent with this role, the channel is inhibited by long-chain acyl-CoA esters and activated by GTP, and these ligands interact with sites that face the cytosol. The work to be summarized shows that KATP channels from mitochondria and plasma membranes are regulated by the same biochemical and pharmacological ligands. We hypothesize that the mitochondrial KATP channel, like its counterparts in the plasma membrane, is heteromultimeric, consisting of a regulatory sulfonylurea receptor (mitoSUR) and an inward-rectifying K+ channel (mitoKIR).
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http://dx.doi.org/10.1016/0005-2728(96)00061-8 | DOI Listing |
J Med Chem
January 2025
Xi'an Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Therapeutics Research, Xi'an 710021, China.
Multidrug-resistant (MDR) bacteria pose a global health threat, underscoring the need for new antibiotics. Lefamulin, the first novel-mechanism antibiotic approved by the FDA in decades, showcases pleuromutilins' promise due to low mutation frequency. However, their clinical use is limited by poor pharmacokinetics and organ toxicity.
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January 2025
Fels Cancer Institute for Personalized Medicine, Department of Cancer & Cellular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca-selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels.
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January 2025
New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China.
Deep brain stimulation technology enables the neural modulation with precise spatial control but requires permanent implantation of conduits. Here, we describe a photothermal wireless deep brain stimulation nanosystem capable of eliminating α-synuclein aggregates and restoring degenerated dopamine neurons in the substantia nigra to treat Parkinson's disease. This nanosystem (ATB NPs) consists of gold nanoshell, an antibody against the heat-sensitive transient receptor potential vanilloid family member 1 (TRPV1), and β-synuclein (β-syn) peptides with a near infrared-responsive linker.
View Article and Find Full Text PDFMol Inform
January 2025
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149, Muenster, Germany.
Primary carnitine deficiency (PCD) is a rare autosomal recessive genetic disorder caused by missense mutations in the SLC22A5 gene encoding the organic carnitine transporter novel type 2 (OCTN2). This study investigates the structural consequences of PCD-causing mutations, focusing on the N32S variant. Using an alpha-fold model, molecular dynamics simulations reveal altered interactions and dynamics suggesting potential mechanistic changes in carnitine transport.
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January 2025
Louvain Institute of Biomolecular Science and Technology, UCLouvain, Croix du Sud, 4-5, bte L7.07.07, B-1348 Louvain-la-Neuve, Belgium.
The iron-regulated surface determinant protein B (IsdB) has recently been shown to bind to toll-like receptor 4 (TLR4), thereby inducing a strong inflammatory response in innate immune cells. Currently, two unsolved questions are (i) What is the molecular mechanism of the IsdB-TLR4 interaction? and (ii) Does it also play a role in nonimmune systems? Here, we use single-molecule experiments to demonstrate that IsdB binds TLR4 with both weak and extremely strong forces and that the mechanostability of the molecular complex is dramatically increased by physical stress, sustaining forces up to 2000 pN, at a loading rate of 10 pN/s. We also show that TLR4 binding by IsdB mediates time-dependent bacterial adhesion to endothelial cells, pointing to the role of this bond in cell invasion.
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