Neutrophil leukocytes have a pivotal function in innate immunity. Dogma dictates that the lethal blow is delivered to microbes by reactive oxygen species (ROS) and halogens, products of the NADPH oxidase, whose impairment causes immunodeficiency. However, recent evidence indicates that the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, K+-rich and alkaline environment in the phagocytic vacuole. Here we show that K+ crosses the membrane through large-conductance Ca2+-activated K+ (BK(Ca)) channels. Specific inhibitors of these channels, iberiotoxin and paxilline, blocked oxidase-induced 86Rb+ fluxes and alkalinization of the phagocytic vacuole, whereas NS1619, a BK(Ca) channel opener, enhanced both. Characteristic outwardly rectifying K+ currents, reversibly inhibited by iberiotoxin, were demonstrated in neutrophils and eosinophils and the expression of the alpha-subunit of the BK channel was confirmed by western blotting. The channels were opened by the combination of membrane depolarization and elevated Ca2+ concentration, both consequences of oxidase activity. Remarkably, microbial killing and digestion were abolished when the BK(Ca) channel was blocked, revealing an essential and unexpected function for this K+ channel in the microbicidal process.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099462 | PMC |
| http://dx.doi.org/10.1038/nature02356 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Channels, Transporters, and Receptors at Membrane Contact Sites.
Contact (Thousand Oaks)
December 2024
Department of Physiology and Membrane Biology, University of California, Davis, CA, USA.
Membrane contact sites (MCSs) are specialized regions where two or more organelle membranes come into close apposition, typically separated by only 10-30 nm, while remaining distinct and unfused. These sites play crucial roles in cellular homeostasis, signaling, and metabolism. This review focuses on ion channels, transporters, and receptors localized to MCSs, with particular emphasis on those associated with the plasma membrane and endoplasmic reticulum (ER).
View Article and Find Full Text PDFSex-specific mechanisms of cerebral microvascular BK dysfunction in a mouse model of Alzheimer's disease.
Alzheimers Dement
December 2024
Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona, USA.
Introduction: Cerebrovascular dysfunction occurs in Alzheimer's disease (AD), impairing hemodynamic regulation. Large conductance Ca-activated K channels (BK) regulate cerebrovascular reactivity and are impaired in AD. BK activity depends on intracellular Ca (Ca sparks) and nitro-oxidative post-translational modifications.
View Article and Find Full Text PDFPurpose: To assess efficacy and safety of URO-902, an investigational gene therapy expressing the α subunit of the large-conductance Ca-activated K channel, in a phase 2a placebo-controlled trial in women with overactive bladder (OAB).
Materials And Methods: Women, age 40 to 79 years, with OAB and urge urinary incontinence who were refractory to OAB medications were randomized to single-dose URO-902 24 and 48 mg or placebo administered by intradetrusor injection by cystoscopy under local anesthesia. Efficacy end points included change from baseline to week 12 in mean daily micturitions, urgency episodes, urge urinary incontinence episodes, and patient-reported outcomes.
Apelin/APJ increased renal blood flow through endothelial BKCa channel induced p-eNOS and ET-1 in diabetic conditions.
Peptides
December 2024
School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address:
Article Synopsis
- Diabetic nephropathy (DN) is linked to renal hemodynamics damage due to dysfunctional endothelial cells and abnormal molecule release, including eNOS and ET-1.
- Apelin, a molecule that affects endothelial cell function, was found to improve renal blood flow in diabetic mice by enhancing eNOS activity and reducing ET-1 levels.
- The study suggests that apelin/APJ increases renal perfusion via the PI3K/AKT/GSK-3β/Nrf2 pathway, influencing the expression of BKCa channel subunits without raising intracellular calcium levels in high glucose environments.
Intranasal oxytocin alleviates postsurgical pain and comorbid anxiety in mice: Participation of BK(Ca) channels in the hippocampus.
Neuropharmacology
March 2025
Department of Anesthesiology and Perioperative Medicine, Fuzong Clinical Medical College (900th Hospital of the Joint Logistic Support Force), Fujian Medical University, Fuzhou, Fujian, PR China.
The affective dimension in postsurgical pain is still poorly understood. Since neuropeptide oxytocin (OXT) has been implicated in a broad spectrum of pain and negative emotion, we investigated the potential therapeutic effect of intranasal OXT on postsurgical pain and associated anxiety in a mice model of plantar incision. The role of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels was explored by using behavioral pharmacology experiments.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!