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Arnaud Chatonnet

Publications and source records attributed to Arnaud Chatonnet.

12 recordsLinked to original sources
PubMed2005

New friendly tools for users of ESTHER, the database of the alpha/beta-hydrolase fold superfamily of proteins.

The structural alpha/beta-hydrolase fold is characterized by a beta-sheet core of five to eight strands connected by alpha-helices to form a alpha/beta/alpha sandwich. The superfamily members, exemplified by the cholinesterases, diverged from a common ancestor into a number of hydrolytic enzymes displaying a wide range of substrate specificities, along with proteins with no recognized hydrolytic activity. In the enzymes, the catalytic triad residues are presented on loops of which one, the nucleophile elbow, is the most conserved feature of the fold. Of the other proteins, which all lack from one to all of the catalytic residues, some may simply be 'inactive' enzymes while others have been shown to be involved in heterologous surface recognition functions. The ESTHER (for esterases, alpha/beta-hydrolase enzymes and relatives) database (http://bioweb.ensam.inra.fr.esther) gathers and annotates all the published pieces of information (gene and protein sequences; biochemical, pharmacological, and structural data) related to the superfamily, and connects them together to provide the bases for studying structure-function relationships within the superfamily. The most recent developments of the database are presented.

Cholinesterases↗
PubMed2005

Synaptic remodeling at the skeletal neuromuscular junction of acetylcholinesterase knockout mice and its physiological relevance.

Acute inhibition of synaptic acetylcholinesterase (AChE) is fatal to normal animals, but AChE-knockout mice (AChE-/-) expressing normal levels of butyrylcholinesterase (BChE) could live to adulthood without AChE expression. The present study was undertaken to determine whether compensatory mechanisms occur in the mutant that allow an effective neuromuscular transmission in the chronic absence of AChE. For this we evaluated neuromuscular transmission and the distribution of nicotinic acetylcholine receptors (nAChRs) and motor nerve terminals on isolated nerve-muscle preparations from AChE-/- mice. AChE-/- hemidiaphragm muscles maintained at 32 degrees C can support muscle twitches, and tetanic contractions during intermittent nerve-stimulation over a wide range of physiological frequencies, even though they develop less force, than age-matched wild-type (AChE+/+) muscles. Tetanic fade in AChE-/- muscles was temperature-sensitive and more marked at 22 degrees C than at 32 degrees C. Inhibition of BChE by tetraisopropylpyrophosphoramide (Iso-OMPA) intensified tetanic fade in AChE-/- muscles, but had no effect on AChE+/+ muscles, suggesting that BChE plays a protective role in nerve terminals. Skeletal muscles from AChE-/- mice adapted to the lack of AChE enzymatic activity by triggering a synaptic remodeling that critically occurred between the second and third week of postnatal development, during synapse elimination. In AChE-/- muscles nAChRs distributed in a smaller and fragmented surface area, that mirrored the branching pattern of motor nerve terminals. These findings indicate that the neuromuscular system exhibits a remarkable plasticity and adaptive responses to the chronic absence of AChE activity that has important consequences for the functioning of the neuromuscular junction.

Acetylcholinesterase↗
PubMed2005

A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterised by lower limb spasticity and weakness. Mutations in NIPA1 (Nonimprinted in Prader-Willi/Angelman syndrome 1) have recently been identified as a cause of autosomal dominant pure HSP, with one mutation described in two unrelated families. NIPA1 has no known function but is predicted to possess nine transmembrane domains and may function as a receptor or transporter. Here we present a large British pedigree in which linkage analysis conclusively demonstrates linkage to the NIPA1 locus (maximum multipoint LOD score 4.6). Subsequent mutation analysis identified a novel missense substitution in a highly conserved NIPA1 residue (G106R) which further confirms a causative link between NIPA1 mutation and autosomal dominant hereditary spastic paraplegia.

Adolescent↗
PubMed2005

Cholinesterase activity in human pulmonary arteries and veins: correlation with mRNA levels.

Isolated intact human pulmonary arteries and veins were used to determine the acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) activities in the absence or presence of two selective cholinesterase (ChE) inhibitors, iso-OMPA or BW284c51, respectively. These results were compared with the mRNA levels for each enzyme in human pulmonary vessels. Total ChE activities measured in presence of acetylthiocholine (ACTI, 1 mM) in intact vascular preparations were 45+/-04 and 114+/-07 mU/g tissue in human pulmonary arteries (n=14) and veins (n=14), respectively. These activities were completely abolished in presence of 10 microM neostigmine. In both types of vessels AChE and BChE activities were observed. These activities were at least 2-fold higher in human pulmonary veins when compared with arteries and were correlated with the accumulation of the corresponding transcripts (n=8). In each type of vessel, similar total ChE activities were detected in homogenized and intact preparations, while in human bronchial preparations this activity was 5-fold higher in homogenates than in intact preparations. Together these results provide evidence that the ChE activities in human pulmonary vessels may be extracellular and that the higher activity measured in veins as compared to arteries was associated with the differential accumulation of the corresponding transcripts.

Acetylcholine↗
PubMed2005

Are there non-catalytic functions of acetylcholinesterases? Lessons from mutant animal models.

Acetylcholinesterase (AChE) hydrolyses acetylcholine (ACh) ensuring the fast clearance of released neurotransmitter at cholinergic synapses. Many studies led to the hypothesis that AChE and the closely related enzyme butyrylcholinesterase (BChE) may play other, non-hydrolytic roles during development. In this review, we compare data from in vivo studies performed on invertebrate and vertebrate genetic models. The loss of function of ache in these systems is responsible for the appearance of several phenotypes. In all aspects so far studied, the phenotypes can be explained by an excess of the undegraded substrate, ACh, leading to misfunction and pathological alterations. Thus, the lack of AChE catalytic activity in the mutants appears to be solely responsible for the observed phenotypes. None of them appears to require the postulated adhesive or other non-hydrolytic functions of AChE.

Acetylcholinesterase↗
PubMed2004

Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase.

We investigated the contributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition to the respiratory dysfunction produced by organophosphates in mice which were adapted or not to low AChE activity. Effects of acute selective inhibition of AChE and BChE on ventilation measured by whole-body plethysmography were compared in mice with either normal AChE activity (wild-type), or mice adapted to a null AChE activity (homozygotes for AChE gene deletion) or adapted to an intermediate level of activity (heterozygotes). In wild-type mice acute reduction of AChE by Huperzine A (1 mg/kg) to the level found in asymptomatic heterozygotes, induced tremors but no respiratory depression, whereas the same dose of Huperzine in heterozygote animals further reduced AChE activity, increased tidal volume (V(T)) and decreased breathing frequency (f(R)). A lethal dose of Huperzine in wild-type mice augmented these respiratory effects, but was ineffective in homozygotes. BChE inhibition by bambuterol was ineffective in wild-type mice and heterozygotes, decreased V(T) in homozygotes adapted to null AChE activity but increased V(T) in wild-type mice acutely treated with Huperzine, also aggravating the cholinergic syndrome. We conclude that: (1) Huperzine does not perturb respiration at a dose inhibiting 40% of AChE, and at a lethal dose does not affect any other enzyme important for respiration; (2) Respiratory function is more sensitive to anticholinesterases in heterozygotes than in wild-type mice; (3) BChE may play distinct roles in respiratory function, because its inhibition has opposite effects on tidal volume depending on whether the mouse has adapted to null AChE or whether AChE has been lowered acutely; (4) BChE inhibition may contribute to the respiratory toxicity of organophosphates.

Acetylcholinesterase↗
PubMed2004

ESTHER, the database of the alpha/beta-hydrolase fold superfamily of proteins.

The alpha/beta-hydrolase fold is characterized by a beta-sheet core of five to eight strands connected by alpha-helices to form a alpha/beta/alpha sandwich. In most of the family members the beta-strands are parallels, but some show an inversion in the order of the first strands, resulting in antiparallel orientation. The members of the superfamily diverged from a common ancestor into a number of hydrolytic enzymes with a wide range of substrate specificities, together with other proteins with no recognized catalytic activity. In the enzymes the catalytic triad residues are presented on loops, of which one, the nucleophile elbow, is the most conserved feature of the fold. Of the other proteins, which all lack from one to all of the catalytic residues, some may simply be 'inactive' enzymes while others are known to be involved in surface recognition functions. The ESTHER database (http://bioweb.ensam.inra.fr/esther) gathers and annotates all the published information related to gene and protein sequences of this superfamily, as well as biochemical, pharmacological and structural data, and connects them so as to provide the bases for studying structure-function relationships within the family. The most recent developments of the database, which include a section on human diseases related to members of the family, are described.

Animals↗
PubMed2003

Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia.

Mast syndrome is an autosomal recessive, complicated form of hereditary spastic paraplegia with dementia that is present at high frequency among the Old Order Amish. Subtle childhood abnormalities may be present, but the main features develop in early adulthood. The disease is slowly progressive, and cerebellar and extrapyramidal signs are also found in patients with advanced disease. Patients have a thin corpus callosum and white-matter abnormalities, as seen on magnetic resonance imaging. Using an extensive Amish pedigree, we have mapped the Mast syndrome locus (SPG21) to a small interval of chromosome 15q22.31 that encompasses just three genes. Sequence analysis of the three transcripts revealed that all 14 affected cases were homozygous for a single base-pair insertion (601insA) in the acid-cluster protein of 33 kDa (ACP33) gene. This frameshift results in the premature termination (fs201-212X213) of the encoded product, which is designated "maspardin" (Mast syndrome, spastic paraplegia, autosomal recessive with dementia), and has been shown elsewhere to localize to intracellular endosomal/trans-Golgi transportation vesicles and may function in protein transport and sorting.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Butyrylcholinesterase and acetylcholinesterase activity and quantal transmitter release at normal and acetylcholinesterase knockout mouse neuromuscular junctions.

1 The present study was performed to evaluate the presence and the physiological consequences of butyrylcholinesterase (BChE) inhibition on isolated phrenic-hemidiaphragm preparations from normal mice expressing acetylcholinesterase (AChE) and BChE, and from AChE-knockout mice (AChE(-/-)) expressing only BChE. 2 Histochemical and enzymatic assays revealed abundance of AChE and BChE in normal mature neuromuscular junctions (NMJs). 3 In normal NMJs, in which release was reduced by low Ca(2+)/high Mg(2+) medium BChE inhibition with tetraisopropylpyrophosphoramide (iso-OMPA) or bambuterol decreased ( approximately 50%) evoked quantal release, while inhibition of AChE with fasciculin-1, galanthamine (10, 20 micro M) or neostigmine (0.1-1 micro M) increased (50-80%) evoked quantal release. Inhibition of both AChE and BChE with galanthamine (80 micro M), neostigmine (3-10 micro M), O-ethylS-2-(diisopropylamino)ethyl-methylphosphono-thioate (MTP) or phospholine decreased evoked transmitter release (20-50%). 4 In AChE(-/-) NMJs, iso-OMPA pre-treatment decreased evoked release. 5 Muscarinic toxin-3 decreased evoked release in both AChE(-/-) and normal NMJs treated with low concentrations of neostigmine, galanthamine or fasciculin-1, but had no effect in normal NMJs pretreated with iso-OMPA, bambuterol, MTP and phospholine. 6 In normal and AChE(-/-) NMJs pretreatment with iso-OMPA failed to affect the time course of miniature endplate potentials and full-sized endplate potentials. 7 Overall, our results suggest that inhibition or absence of AChE increases evoked quantal release by involving muscarinic receptors (mAChRs), while BChE inhibition decreases release through direct or indirect mechanisms not involving mAChRs. BChE apparently is not implicated in limiting the duration of acetylcholine action on postsynaptic receptors, but is involved in a presynaptic modulatory step of the release process.

Acetylcholinesterase↗
PubMed2003

Respiratory survival mechanisms in acetylcholinesterase knockout mouse.

Cholinergic neurotransmission ensures muscle contraction and plays a role in the regulation of respiratory pattern in the brainstem. Inactivation of acetylcholinesterase (AChE) by organophosphates produces respiratory failure but AChE knockout mice survive to adulthood. Respiratory adaptation mechanisms which ensure survival of these mice were examined in vivo by whole body plethysmography and in vitro in the neonatal isolated brainstem preparation. AChE-/- mice presented no AChE activity but unaffected butyrylcholinesterase (BChE) activity. In vivo, bambuterol (50-500 microg/kg s.c.) decreased BChE activity peripherally but not in brain tissue and induced apnea and death in adult and neonate AChE-/- mice without affecting littermate AChE+/+ and +/- animals. In vitro, bath-applied bambuterol (1-100 microm) and tetraisopropylpyrophosphoramide (10-100 microm) decreased BChE activity in the brainstem but did not perturb central respiratory activity recorded from spinal nerve rootlets. In vitro, the cholinergic agonists muscarine (50-100 microm) and nicotine (0.5-10 microm) induced tonic activity in respiratory motoneurons and increased the frequency of inspiratory bursts in AChE+/+ and +/- animals. These effects were greatly attenuated in AChE-/- animals. The results suggest that, in mice lacking AChE, (i) BChE becomes essential for survival peripherally but plays no critical role in central rhythm-generating structures and (ii) a major adaptive mechanism for respiratory survival is the down-regulated response of central respiratory-related neurons and motoneurons to muscarinic and nicotinic agonists.

Acetylcholinesterase↗
PubMed2002

Acetylcholinesterase is required for neuronal and muscular development in the zebrafish embryo.

The neurotransmitter acetylcholine (ACh) has a crucial role in central and neuromuscular synapses of the cholinergic system. After release into the synaptic cleft, ACh is rapidly degraded by acetylcholinesterase (AChE). We have identified a mutation in the ache gene of the zebrafish, which abolishes ACh hydrolysis in homozygous animals completely. Embryos are initially motile but subsequently develop paralysis. Mutant embryos show defects in muscle fiber formation and innervation, and primary sensory neurons die prematurely. The neuromuscular phenotype in ache mutants is suppressed by a homozygous loss-of-function allele of the alpha-subunit of the nicotinic acetylcholine receptor (nAChR), indicating that the impairment of neuromuscular development is mediated by activation of nAChR in the mutant. Here we provide genetic evidence for non-classical functions of AChE in vertebrate development.

Acetylcholinesterase↗