Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors

Zoli, Michèle; Pucci, Susanna; Vilella, Antonietta; Gotti, Cecilia

doi:10.2174/1570159x15666170912110450

Cited by 200 publications

(246 citation statements)

References 122 publications

(150 reference statements)

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“…In humans, there are 16 different subunits encoded be separate genes, and the nAChRs are both homomeric and heteromeric. The nAChR is coupled to non‐selective cation channels and, dependent on subunit composition it transports sodium, potassium and in some instances calcium (Colquhoun et al., ; Zoli et al., ). The mAChR form G protein‐coupled receptor complexes in the cell membranes of certain neurons, i.e.…”

Section: Assessmentmentioning

confidence: 99%

Scientific opinion on the risks for animal and human health related to the presence of quinolizidine alkaloids in feed and food, in particular in lupins and lupin‐derived products

Schrenk¹,

Bodin²,

Chipman³

et al. 2019

EFS2

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The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of quinolizidine alkaloids (QAs) in feed and food. This risk assessment is limited to QAs occurring in Lupinus species/varieties relevant for animal and human consumption in Europe (i.e. Lupinus albus L., Lupinus angustifolius L., Lupinus luteus L. and Lupinus mutabilis Sweet). Information on the toxicity of QAs in animals and humans is limited. Following acute exposure to sparteine (reference compound), anticholinergic effects and changes in cardiac electric conductivity are considered to be critical for human hazard characterisation. The CONTAM Panel used a margin of exposure (MOE) approach identifying a lowest single oral effective dose of 0.16 mg sparteine/kg body weight as reference point to characterise the risk following acute exposure. No reference point could be identified to characterise the risk of chronic exposure. Because of similar modes of action for QAs, the CONTAM Panel used a group approach assuming dose additivity. For food, the highest mean concentration of Total QAs (TotQAs) (i.e. the 6 most abundant QAs) was found in lupin seed samples classified as 'Lupins (dry) and similar-'. Due to the limited data on occurrence and consumption, dietary exposure was calculated for some specific scenarios and no full human health risk characterisation was possible. The calculated margin of exposures (MOEs) may indicate a risk for some consumers. For example, when lupin seeds are consumed without a debittering step, or as debittered lupin seeds high in QA content and when 'lupin-based meat imitates' are consumed. For horses, companion and farm animals, other than salmonids, the available database on adverse effects was too limited to identify no-observed-adverse-effect levels and/or lowest-observed-adverse-effect levels and no risk characterisation was possible. For salmonids, the CONTAM Panel considers the risk for adverse effects to be low.This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made.The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. Quinolizidine alkaloids in feed and food www.efsa.europa.eu/efsajournal 2 EFSA Journal 2019;17(11):5860 Quinolizidine alkaloids in feed and food www.efsa.europa.eu/efsajournal 3 EFSA Journal 2019;17(11):5860lupanine or 13a-OH-lupanine (each equivalent to 0.14 mg/kg bw for a person with a body weight of 70 kg). Human cases of poisoning with lupin seeds are infrequent and rarely lead to a fatal outcome. However, case reports of poisoning in children suggest that these are more susceptible to intoxication than adults, and doses of lupin alkaloids from 10 mg/kg bw onwards may be lethal. Intoxication have been associated with inadequate debittering of lupin seeds by consumers, while no case of poisoning has been...

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Section: Assessmentmentioning

confidence: 99%

Scientific opinion on the risks for animal and human health related to the presence of quinolizidine alkaloids in feed and food, in particular in lupins and lupin‐derived products

Schrenk¹,

Bodin²,

Chipman³

et al. 2019

EFS2

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“…The nicotinic acetylcholine receptor (nAChR) is well known as a member of the ligand‐dependent superfamily of ion channels and can be found in neuronal cells. It is involved in several processes related to cognitive function, learning, memory, motor coordination, and analgesia …”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

“…Moreover, α7 nAChR takes part in complex cholinergic anti‐inflammatory pathways and therefore in neuroinflammation, which is a precursor event in the development of AD. In general terms, this process may be responsible for elevating abnormal Aβ and tau protein aggregation . Hence, inhibitors of α7 nAChR have become an attractive option for designing drug candidates for AD…”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

“…PAMs of α7 nAChR are of great importance because they increase the potency of natural agonists (ACh, for example), altering the conformation of the receptor structure to a more activate state . They also have higher selectivity because they interact with less conserved and more specific allosteric sites, diminish tolerance caused by rapid desensitization of α7, and also act as neuroprotectors …”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

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Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

et al. 2019

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Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β‐amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.

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“…The biology of the nicotinic pathway supports the importance of studying gene-gene interaction to better consider its influence on complex traits such as tobacco smoking. Notably, essential to nAChR function are enzymes that metabolize acetylcholine (nAChR endogenous ligand) and trafficking/chaperone proteins [8][9][10] that have been overlooked to date in genetic studies focusing on nAChR genes. Interactions between CHRNA4 and genes from the Bdnf pathway have been associated with the AAO [11] and the presence of nicotine dependence [12,13].…”

Section: Introductionmentioning

confidence: 99%

Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders

Icick

Besson

Zerdazi

et al. 2019

Preprint

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Introduction: Tobacco smoking is a major health burden worldwide, especially in populations suffering from other substance use disorders (SUDs). Several smoking phenotypes have been associated with single nucleotide polymorphisms (SNPs) of nicotinic acetylcholine receptors (nAChRs). Yet, little is known about the genetics of tobacco smoking in populations with other SUDs, particularly regarding gene-gene interactions and pleiotropy, which are likely involved in the polygenic architecture of SUDs. Thus, we undertook a candidate pathway association study of nAChR-related genes and smoking phenotypes in a sample of SUD patients.Methods: 493 patients with genetically-verified Caucasian ancestry were characterized extensively regarding patterns of tobacco smoking, other SUDs, and 83 SNPs from the nicotinic pathway, encompassing all brain nAChR subunits and metabolic/chaperone/trafficking proteins. Single-SNP, gene-based and SNP x SNP interactions analyses were performed to investigate associations with relevant tobacco smoking phenotypes. This included Bayesian analyses to detect pleiotropy, and adjustment on clinical and sociodemographic confounders. Results:After multiple adjustment, we found independent associations between CHRNA3 rs8040868 and a higher number of cigarettes per day (CPD), and between RIC3 rs11826236 and a lower age at smoking initiation. Two SNP x SNP interactions were associated with age at onset (AAO) of daily smoking. There was pleiotropy regarding three SNPs in CHRNA3 (CPD, AAO daily smoking), ACHE (CPD, HSI) and CHRNB4 (CPD, both AAOs). Discussion:Despite limitations, the present study shows that the genetics of tobacco smoking in SUD patients are both distinct and partially shared across smoking phenotypes, and involve metabolic and chaperone effectors of the nicotinic pathway.

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Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors

Cited by 200 publications

References 122 publications

Scientific opinion on the risks for animal and human health related to the presence of quinolizidine alkaloids in feed and food, in particular in lupins and lupin‐derived products

Scientific opinion on the risks for animal and human health related to the presence of quinolizidine alkaloids in feed and food, in particular in lupins and lupin‐derived products

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders

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