A5034552370- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Alzheimer's disease research and treatments
- Economic and Environmental Valuation
- Genomics and Chromatin Dynamics
- Pluripotent Stem Cells Research
- RNA Research and Splicing
- Experimental Behavioral Economics Studies
- Neuropeptides and Animal Physiology
- Climate Change Policy and Economics
- Fiscal Policy and Economic Growth
- Genetic Neurodegenerative Diseases
- Global Health Care Issues
- Epigenetics and DNA Methylation
- Neurogenesis and neuroplasticity mechanisms
- Nicotinic Acetylcholine Receptors Study
- Cardiac electrophysiology and arrhythmias
- CRISPR and Genetic Engineering
- Genetics and Neurodevelopmental Disorders
- Employment and Welfare Studies
- Dementia and Cognitive Impairment Research
- Bioinformatics and Genomic Networks
- Health disparities and outcomes
- Adenosine and Purinergic Signaling
University of Oxford
2015-2024
York University
2007-2024
Liverpool Hope University
2013-2024
Kavli Energy NanoScience Institute
2023-2024
King's College London
2008-2023
AstraZeneca (United Kingdom)
2022
Warneford Hospital
2015-2019
National Institute of Anthropology and History
2013
University of Leeds
2000-2006
McMaster University
1999-2004
Complementary DNAs for three different muscarinic acetylcholine receptors were isolated from a rat cerebral cortex library, and the cloned expressed in mammalian cells. Analysis of human genomic clones indicates that there are at least four functional receptor genes these lack introns coding sequence. This gene family provides new basis evaluating diversity mechanisms nervous system.
A family of five cholinergic muscarinic receptor genes (m1, m2, m3, m4, and m5) has recently been identified cloned. In order to investigate the pharmacological properties individual receptors, we have transfected each these into Chinese hamster ovary cells (CHO-K1) established stable cell lines expressing receptor. present study examined antagonist binding Antagonists were chosen that had previously proposed be selective for subtypes included pirenzepine, AF-DX 116, methoctramine,...
A family of 4 rat muscarinic receptors (m1, m2, m3, and m4) have recently been cloned sequenced (Bonner et al., 1987). Since pharmacological probes that are presently available do not appear to distinguish among 3 these receptors, we constructed oligonucleotide corresponding the N-terminal sequences used them specifically localize m1, m4 mRNA in sections brain using situ hybridization histochemistry. Northern analysis demonstrated a 3.1 kilobase (kb) m 1 mRNA, 4.5 kb m3 3.3 cerebral cortex,...
The completion of whole genome sequencing projects has provided the genetic instructions life. However, whereas identification gene coding regions progressed, mapping transcriptional regulatory motifs moved more slowly. To understand how distinct expression profiles can be established and maintained, a greater understanding these sequences their trans-acting factors is required. Herein we have used combined in silico biochemical approach to identify binding sites [repressor element...
Proneural genes such as Ascl1 are known to promote cell cycle exit and neuronal differentiation when expressed in neural progenitor cells. The mechanisms by which proneural activate neurogenesis--and, particular, the that they regulate--however, mostly unknown. We performed a genome-wide characterization of transcriptional targets embryonic brain stem cultures location analysis expression profiling embryos overexpressing or mutant for Ascl1. wide range molecular cellular functions...
A diverse set of biological processes have been implicated in the pathophysiology Alzheimer's disease (AD) and related dementias. However, there is limited understanding peripheral mechanisms relevant earliest phases disease. Here, we used a large-scale proteomics platform to examine association 4877 plasma proteins with 25-year dementia risk 10,981 middle-aged adults. We found 32 dementia-associated that were involved proteostasis, immunity, synaptic function, extracellular matrix...
The ionotropic ATP receptor subunits P2X<sub>1–6</sub> receptors play important roles in synaptic transmission, yet the P2X<sub>7</sub>receptor has been reported as absent from neurons normal adult brain. Here we use RT-PCR to demonstrate that transcripts for P2X<sub>7</sub> are present extracts medulla oblongata, spinal cord, and nodose ganglion. Using <i>in situ</i> hybridization mRNA encoding, was detected numerous throughout oblongata cord. Localizing protein with immunohistochemistry...
Huntingtin is a protein that mutated in Huntington9s disease (HD), dominant inherited neurodegenerative disorder. We previously proposed that, addition to the gained toxic activity of mutant protein, selective molecular dysfunctions HD may represent consequences loss wild-type activity. first reported huntingtin positively affects transcription brain-derived neurotrophic factor (<i>BDNF</i>) gene, cortically derived survival for striatal neurons are mainly affected disease. Mutation...
Abstract Although originally cloned from rat brain, the P2X 7 receptor has only recently been localized in neurones, and functional responses mediated by these neuronal receptors (P2X R) are largely unknown. Here we studied effect of R activation on release neurotransmitters superfused hippocampal slices. ATP (1–30 m ) other analogues elicited concentration‐dependent [ 3 H]GABA outflow, with following rank order potency: benzoylbenzoylATP (BzATP) > ADP. PPADS, non‐selective P2‐receptor...
We have carried out an extensive pharmacological characterization of muscarinic binding sites in rabbit lung and chicken heart parallel with M1, M2, M3 sites, [3H]Pirenzepine, a selective antagonist at M1 receptors, bound saturably reversibly to membranes from lung. These were not however, because the cardioselective himbacine had 10-fold higher affinity these than [3H]pirenzepine rat cortex (true sites). measured inhibitory potency 28 antagonists [3H]N-methylscopolamine-labeled heart, lung,...
AbstractA large number of neuron-specific genes characterized to date are under the control negative transcriptional regulation. Many promoter regions possess repressor element 1/neuron-restrictive silencing (RE1/NRSE). Its cognate binding protein, REST/NRSF, is an essential transcription factor; its null mutations result in embryonic lethality, and dominant mutants produce aberrant expression genes. REST/NRSF acts as a regulator gene both nonneuronal tissue developing neurons. Here, we...
The maintenance of pluripotency and specification cellular lineages during embryonic development are controlled by transcriptional regulatory networks, which coordinate specific sets genes through both activation repression. repressor RE1-silencing transcription factor (REST) plays important but distinct roles in (ESC) neural (NSC) stem cells. We investigated how these biological effected at a genomic level. present integrated, comparative genome- transcriptome-wide analyses networks...
The proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how interacts with chromatin landscape regulate when promoting differentiation. We find that binding occurs mostly at distal enhancers is associated activation transcription. Surprisingly, accessibility its sites neural stem/progenitor cells remains largely unchanged throughout...
Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models chronic inflammatory pain. The aim this study was determine whether these compounds could also affect neuropathic Different class I HDACIs were delivered intrathecally into rat spinal cord traumatic nerve injury antiretroviral drug-induced peripheral neuropathy (stavudine, d4T). Mechanical thermal hypersensitivity attenuated by 40% 50% as a...
Differentiation of pluripotent embryonic stem (ES) cells through multipotent neural (NS) into differentiated neurons is accompanied by wholesale changes in transcriptional programs. One factor that present at all three stages and a key to neuronal differentiation the RE1-silencing transcription (REST/NRSF). Here, we have used novel chromatin immunoprecipitation-based cloning strategy (SACHI) identify 89 REST target genes ES cells, hippocampal NS mature hippocampus. The gene products are...
A family of genes encoding four distinct muscarinic receptors (designated m1-m4) has been cloned and stably expressed in A9 L cells. When the m1 m3 were stimulated with carbachol, there was a rapid rise liberated arachidonic acid, inositol phosphates, cAMP, while m2 m4 receptor stimulation had no detectable these second messengers. Pretreatment phorbol 12-myristate 13-acetate (PMA) caused marked acceleration amplification receptor-mediated acid release. In contrast, m1- m3-mediated phosphate...
1. Microinjection of selective antibodies into superior cervical ganglion (SCG) neurones has identified the G‐protein alpha‐subunits mediating muscarinic receptor inhibition M‐type K+ current (IK(M)) and alpha‐adrenoceptor Ca2+ (ICa). 2. Antibodies specific for G alpha q/11, but not those o, reduced M‐current by agonist oxotremorine‐M, whereas anti‐G o antibodies, q/11 or i1‐3 calcium noradrenaline. 3. Immunoblots with anti‐G‐protein demonstrated presence both q 11, while o1 (but virtually...