A5101864581- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Neuroscience and Neural Engineering
- Pain Mechanisms and Treatments
- Photoreceptor and optogenetics research
- Multiple Sclerosis Research Studies
- Cardiac electrophysiology and arrhythmias
- Ion Channels and Receptors
- Neuroscience of respiration and sleep
- Alzheimer's disease research and treatments
- Neurobiology and Insect Physiology Research
- Muscle activation and electromyography studies
- Lipid Membrane Structure and Behavior
- Mechanical and Optical Resonators
- Olfactory and Sensory Function Studies
- Connexins and lens biology
- Restless Legs Syndrome Research
- Drug Transport and Resistance Mechanisms
- Stress Responses and Cortisol
- Gastrointestinal motility and disorders
- Fungal Plant Pathogen Control
- Electrochemical Analysis and Applications
- Adenosine and Purinergic Signaling
- Vagus Nerve Stimulation Research
- Cholinesterase and Neurodegenerative Diseases
Queen Mary University of London
2011-2024
University of Cambridge
2021
William Harvey Research Institute
2013
University College London
1987-2009
London Cancer
2004
Medawar Building for Pathogen Research
2003
National Hospital for Neurology and Neurosurgery
1987-1999
Yale University
1993-1996
Sobell House
1988
1. The nature, distribution and function of rectifying channels in rat spinal root myelinated axons has been assessed with selective blocking agents a variety intracellular extracellular recording techniques. 2. electrotonic responses roots poisoned tetrodotoxin (TTX) to constant current pulses had fast (rise time much less than 1 ms) slow components, which were interpreted terms Barrett & Barrett's (1982) revised cable model for nerve. Depolarization evoked rapid outward rectification...
A central hallmark of Alzheimer's disease is the presence extracellular amyloid plaques chiefly consisting amyloid-β (Aβ) peptides in brain interstitium. Aβ largely exists two isoforms, 40 and 42 amino acids long, but a large body evidence points to Aβ(1-42) rather than Aβ(1-40) as cytotoxic form. One proposed mechanism by which exerts toxicity formation ion channel pores that disrupt intracellular Ca2+ homeostasis. However, previous studies using membrane mimetics have not identified any...
1. We have investigated the origin of post‐ischaemic ectopic discharges in human nerve by recording changes electrical excitability following periods ischaemia (15‐20 min) sufficient to induce spontaneous motor fasciculations. The ulnar was stimulated beneath a pressure cuff on upper arm, and compound action potentials recorded from abductor digiti minimi. 2. On releasing after 15 min ischaemia, thresholds short current pulses increased two distinct phases: slow phase followed rapid rise...
Graphical Abstract figure legend HCN channels play an evolutionarily conserved pacemaker role in renal pelvic smooth muscle (RPSM) of lower and higher order mammals. The function hyperpolarization-activated cation (HCN) pacemakers remains controversial. Renal trigger contractions that expel waste from the kidney, have been localized to these tissues. To date, however, mechanisms underlying RPSM activity remain elusive. was investigated both (top left) (bottom mammalian models, which exhibit...
Peripheral pain thresholds are regulated by the actions of inflammatory mediators. Some act through G-protein-coupled receptors on voltage-gated sodium channels. We have found that a low-threshold, persistent tetrodotoxin-resistant Na+ current, attributed to NaV1.9, is upregulated GTP and its non-hydrolysable analogue GTP-gamma-S, but not GDP. Inclusion GTP-gamma-S (500 microM) in internal solution led an increase maximal current amplitude > 300 % within 5 min. In clamp, upregulation was...
Persistent tetrodotoxin-resistant (TTX-r) sodium currents up-regulated by intracellular GTP have been invoked as the site of action peripheral inflammatory mediators that lower pain thresholds, and ascribed to Na(V)1.9 channel. Here we describe properties a global knock-out produced replacing exons 4 5 in SCN11A with neomycin resistance cassette, deleting domain 1 voltage sensor introducing frameshift mutation. Recordings from small (< 25 microm apparent diameter) sensory neurones indicated...
Activation of visceral nociceptors by inflammatory mediators contributes to hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine pyrimidine nucleotides (e.g., ATP UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation the gut, immune inflammation. Actions mediated through both ionotropic P2X receptors metabotropic P2Y receptors. receptor activation causes excitation afferents; however,...
The tetrodotoxin-resistant (TTX-r) persistent Na(+) current, attributed to Na(V)1.9, was recorded in small (< 25 mum apparent diameter) dorsal root ganglion (DRG) neurones cultured from P21 rats and adult wild-type Na(V)1.8 null mice. In conventional whole-cell recordings intracellular GTP-gamma-S caused current up-regulation, an effect inhibited by the PKC pseudosubstrate inhibitor, PKC19-36. amplitude also up-regulated microM 1-oleoyl-2-acetyl-sn-glycerol (OAG) consistent with involvement....
1. We have provoked ectopic discharges from demyelinated rat spinal roots by applying 1 mM‐4‐aminopyridine (4‐AP), and recorded membrane currents action potentials extracellularly spike‐triggered averaging. The demyelination was caused intrathecal injection of diphtheria toxin, 6‐9 days previously. 2. Mapping the distribution in vicinity an site showed that most cases (eight out twelve recorded) impulses arose one end a continuously conducting internode, conducted both directions. In...
1. The mechanism of post‐ischaemic ectopic impulse generation in nerve is not known, and previous measurements excitability changes human motor axons have appeared to conflict. We used automatic threshold tracking different stimulus‐response combinations follow the effects on brief (5‐10 min) periods ischaemia, too short induce fasciculations. Excitability been compared at sites innervating hand, arm foot muscles. 2. Threshold was determined as percutaneous stimulus current required excite a...
TRPV1 is a member of the transient receptor potential ion channel family and gated by capsaicin, pungent component chili pepper. It expressed predominantly in small diameter peripheral nerve fibers activated noxious temperatures >42 °C. 20-Hydroxyeicosatetraenoic acid (20-HETE) cytochrome P-450 4A/4F-derived metabolite membrane phospholipid arachidonic acid. powerful vasoconstrictor has structural similarities with other agonists, e.g. hydroperoxyeicosatetraenoic 12-HPETE, we hypothesized...
Voltage-gated sodium channels (VGSCs) play a key role in the initiation and propagation of action potentials neurons. Na(V)1.8 is tetrodotoxin (TTX) resistant VGSC expressed nociceptors, peripheral small-diameter neurons able to detect noxious stimuli. underlies vast majority currents during potentials. Many studies have highlighted for inflammatory chronic pain models. Lipid rafts are microdomains plasma membrane highly enriched cholesterol sphingolipids. tune spatial temporal organisation...
1. We have previously studied accommodation in rat and human motor axons by testing excitability with combinations of long short current pulses. found that normally polarized accommodate slowly partially (over about 50 ms) to subthreshold depolarizing currents, the principal mechanism is activation slow potassium channels (Bostock & Baker, 1988). To understand response nerves ischaemia, we now extended these observations already depolarized before currents were applied. 2. Rat ventral...
<h3>Background</h3> Conditions characterised by chronic visceral pain represent a significant healthcare burden with limited treatment options. While animal models have provided insights into potential mechanisms of nociception and identified candidate drug targets, these not translated successful treatments in humans. <h3>Objective</h3> To develop an vitro afferent nerve preparation using surgically excised freshly isolated human colon vermiform appendix-mesentery tissues. <h3>Methods</h3>...
Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative trial designs are required to hasten the translational process of drug development. An ideal target monitor efficacy strategies aimed at treating multiple visual system, which most accessible part human central nervous system. A novel C57BL/6 mouse line was generated expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell...
1. Delayed rectifier K+ currents were studied in Schwann cells cultured from neonatal rabbit sciatic nerves with the whole‐cell patch‐clamp technique. 2. Depolarizing voltage steps (40 ms duration) activated two types of current: type I, whose apparent activation threshold was about ‐60 mV (half‐maximal conductance at ‐40 +/‐ 1 mV, n = 10); and II, ‐25 + 11 9). 3. Type I current blocked by alpha‐dendrotoxin (alpha‐DTX) an equilibrium dissociation constant (KD) 1.3 nM, whereas II unaffected...
Altered expression of voltage-gated sodium, calcium and potassium channels has been associated with neuropathic pain conditions. In addition, roles for the ligandgated P2X3 NMDA receptors, as well pacemaker HCN have also invoked in pathogenesis pain. this chapter, evidence an important role post-translational regulation Nav1.9 setting thresholds is presented. Despite importance tactile allodynia mechanical hyperalgesia chronic pain, we remain ignorant molecular nature mechanosensors present...
Sensory neurone subtypes (≤ 25 μm apparent diameter) express a variety of Na + channels, where expression is linked to action potential duration, and associated with differential IB4‐lectin binding. We hypothesized that sensitivity ATX‐II might also discriminate neurones report 1 μ m has negligible or small effects on potentials in IB4 +ve, but dramatically increased duration −ve, neurones. The toxin did not act tetrodotoxin‐resistant (TTX‐r) V 1.8 currents; discrimination was based...
Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R synthesized an anandamide (endocannabinoid) analogue in anti-metabolite approach identify drugs target spasticity.Following chemistry, variety biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays vivo animal models, were used...