A5064518084- Erythrocyte Function and Pathophysiology
- Blood properties and coagulation
- Ion channel regulation and function
- Ion Channels and Receptors
- Marine Sponges and Natural Products
- Adenosine and Purinergic Signaling
- Neurobiology and Insect Physiology Research
- Neonatal Health and Biochemistry
- Phytochemicals and Antioxidant Activities
- Calcium signaling and nucleotide metabolism
- Nerve injury and regeneration
- Postharvest Quality and Shelf Life Management
- Cardiac electrophysiology and arrhythmias
- Phytochemical compounds biological activities
- Chemical synthesis and alkaloids
- Heavy Metals in Plants
- Heavy Metal Exposure and Toxicity
- Nicotinic Acetylcholine Receptors Study
- Pancreatic function and diabetes
- Hemoglobinopathies and Related Disorders
- Phytochemical Studies and Bioactivities
- Biochemical Analysis and Sensing Techniques
- Trace Elements in Health
- Hemoglobin structure and function
- Electrochemical sensors and biosensors
University of Leeds
2014-2023
University of Leicester
2008-2009
Abstract Mammalian biology adapts to physical activity but the molecular mechanisms sensing remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force enable vascular development. Here, we address in adult endothelium, major control site activity. Mice without endothelial lack obvious phenotype close inspection reveals a specific effect on endothelium-dependent relaxation mesenteric resistance artery. Strikingly, is required for elevated blood pressure during...
Abstract Two prominent concepts for the sensing of shear stress by endothelium are PIEZO1 channel as a mediator mechanically activated calcium ion entry and PECAM1 cell adhesion molecule apex triad with CDH5 VGFR2. Here, we investigated if there is relationship. By inserting non-disruptive tag in native mice, reveal situ overlap PECAM1. Through reconstitution high resolution microscopy studies show that interacts directs it to cell-cell junctions. extracellular N-terminus critical this, but...
Current therapies for common types of cancer such as renal cell are often ineffective and unspecific, novel pharmacological targets approaches in high demand. Here we show the unexpected possibility rapid selective killing cells through activation calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by sesquiterpene (-)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, direct stimulator TRPC4 TRPC5 channels....
The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist, but the pharmacology of these channels otherwise limited.Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca2+ Tl+ measurements made HEK 293 or CHO cell lines overexpressing subunits HUVECs, which natively express Piezo1. Isometric tension recordings from rings mouse thoracic aorta.Modification pyrazine ring yielded an analogue, lacked agonist...
Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however, its role in the heart poorly understood. Cardiac fibroblasts help preserve myocardial integrity and play key regulating repair remodeling following stress or injury. Here we investigated expression function cultured human mouse cardiac fibroblasts. RT-PCR experiments confirmed that mRNA expressed at levels similar to those endothelial cells. The results of Fura-2 intracellular Ca2+ assay validated...
(-)-Englerin A ((-)-EA) has a rapid and potent cytotoxic effect on several types of cancer cell that is mediated by plasma membrane ion channels containing transient receptor potential canonical 4 (TRPC4) protein. Because these are Ca2+-permeable, it was initially thought the cytotoxicity arose as consequence Ca2+ overload. Here we show this not case (-)-EA heteromer TRPC4 TRPC1 proteins. Both were required for cytotoxicity; however, although necessary (-)-EA-evoked elevation, not. either...
Piezo1 forms a mechanically activated calcium-permeable nonselective cation channel that is functionally important in many cell types. Structural data exist for C-terminal regions, but we lack information about N-terminal regions and how the entire interacts with lipid bilayer. Here, use computational approaches to predict three-dimensional structure of full-length simulate it an asymmetric membrane. A number novel insights are suggested by model: 1) creates trilobed dome membrane extends...
Background and Purpose The protein PIEZO1 forms mechanically activated, calcium‐permeable, non‐selective cation channels in numerous cell types from several species. Options for pharmacological modulation are limited so we modified a small‐molecule agonist at (Yoda1) to increase the ability modulate these channels. Experimental Approach Medicinal chemistry generated Yoda1 analogues that were tested intracellular calcium patch‐clamp assays on cultured cells exogenously expressing human or...
Background and Purpose The TRPC5 proteins assemble to create calcium‐permeable, non‐selective, cationic channels. We sought novel modulators of these channels through studies natural products. Experimental Approach Intracellular calcium measurements patch clamp recordings were made from cell lines. Compounds generated by synthetic chemistry. Key Results Through a screen products used in traditional Chinese medicines, the flavonol galangin was identified as an inhibitor lanthanide‐evoked...
Background and Purpose The TRPC1, TRPC4, TRPC5 proteins form homotetrameric or heterotetrameric, calcium‐permeable cation channels that are involved in various disease states. Recent research has yielded specific potent xanthine‐based TRPC1/4/5 inhibitors. Here, we investigated the possibility of activators these channels. Experimental Approach An analogue inhibitor Pico145, AM237, was synthesized its activity using HEK cells overexpressing TRPC5, TRPC4–C1, TRPC5–C1, TRPC1:C4 TRPC1:C5...
KEYWORDS: anxietycalcium ioncardiac remodellingenglerinepilepsynon-selective cationic channelpainpharmacologysodium ionTransient Receptor Potential
Abstract Current therapies for common types of cancer such as renal cell are often ineffective and unspecific, novel pharmacological targets approaches in high demand. Here we show the unexpected possibility rapid selective killing cells through activation calcium‐permeable nonselective transient receptor potential canonical (TRPC) calcium channels by sesquiterpene (−)‐englerin A. This compound was found to be a highly efficient, fast‐acting, potent, selective, direct stimulator TRPC4 TRPC5...
Background and Purpose The diterpene ester tonantzitlolone (TZL) is a natural product, which displays cytotoxicity towards certain types of cancer cell such as renal carcinoma cells. effect similar to that (‐)‐englerin A, so, although it chemically distinct, we investigated whether TZL also targets transient receptor potential canonical (TRPC) channels the 1, 4 5 type (TRPC1/4/5 channels). Experimental Approach effects on A498 cells natively expressing TRPC1 TRPC4, modified HEK293...
Indicative of cell surface P2X ion channel activation, extracellular ATP evokes a rapid and transient calcium influx in the model eukaryote Dictyostelium discoideum. Five P2X-like proteins (dP2XA–E) are present this organism. However, their roles purinergic signaling unclear, because dP2XA proved to have an intracellular localization on contractile vacuole where it is thought be required for osmoregulation. To determine functional properties remaining four dP2X-like assess cellular roles, we...
The presence of five P2X-like genes (p2xA–E) in Dictyostelium suggests that nucleotides other than cAMP may act as extracellular signalling molecules this model eukaryote. However, p2xA was found to have an exclusively intracellular localisation making it unclear whether utilise P2 receptors a manner analogous vertebrates. Using apoaequorin expressing strain we show here do possess cell surface facilitate Ca2+ influx response ATP and ADP (EC50 = 7.5 μM 6.1 μM, respectively). Indicative P2X...
PIEZO1 channels are mechanically activated cation that play a pivotal role in sensing mechanical forces various cell types. Their dysfunction has been associated with numerous pathophysiological states, including generalized lymphatic dysplasia, varicose vein disease, and hereditary xerocytosis. Given their physiological relevance, investigating is crucial for the pharmaceutical industry, which requires scalable techniques to allow drug discovery. In this regard, several studies have used...
The hERG potassium channel is critical for repolarisation of the cardiac action potential. Reduced expression at plasma membrane, whether caused by hereditary mutations or drugs, results in long QT syndrome and increases risk ventricular arrhythmias. Thus, it fundamental importance to understand how density this membrane regulated. We used antibodies an extracellular native engineered epitope, conjunction with immunofluorescence ELISA, investigate mechanism endocytosis recombinant cells...
ABSTRACT Fatality from coronavirus disease 19 (COVID-19) is a major problem globally and so identification of its underlying molecular mechanisms would be helpful. The combination COVID-19 clinical data genome sequence information providing potential route to such mechanisms. Here we took candidate gene approach UK Biobank based on the suggested roles endothelium membrane proteins in COVID-19. We focussed PIEZO1 gene, which encodes non-selective cation channel that mediates endothelial...
ABSTRACT Generalised Lymphatic Dysplasia (GLD) is characterised by widespread lymphoedema, with at least one of the following: fetal hydrops, intestinal or pulmonary lymphangiectasia, pleural effusions, pericardial effusions and ascites. Satisfactory medical therapies are lacking. A genetic association has been identified that prevents expression surface trafficking PIEZO1, a subunit mechanically activated calcium-permeable channels. However, PIEZO1 large highly polymorphic gene...
Abstract Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however its role in the heart poorly understood. Cardiac fibroblasts are responsible for preserving structural integrity of myocardium and play key regulating repair remodeling following stress or injury. We investigated expression function cultured human mouse cardiac fibroblasts. RT-PCR studies confirmed mRNA at similar levels to endothelial cells. Fura-2 intracellular Ca 2+ measurements...