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Nicotinic receptors in non-human primates: Analysis of genetic and functional conservation with humans.

ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are highly conserved between humans and non-human primates. Conservation exists at the level of genomic structure, protein structure and epigenetics. Overall homology of nAChRs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. In addition to conservation at the protein level, there is high conservation of genomic structure in terms of intron and exon size and placement of CpG sites that play a key role in epigenetic regulation. Analysis of single nucleotide polymorphisms (SNPs) shows that while the majority of SNPs are not conserved between humans and macaques, some functional polymorphisms are. Most significantly, cynomolgus monkeys express a similar ?5 nAChR Asp398Asn polymorphism to the human ?5 Asp398Asn polymorphism that has been linked to greater nicotine addiction and smoking related disease. Monkeys can be trained to readily self-administer nicotine, and in an initial study we have demonstrated that cynomolgus monkeys bearing the ?5 D398N polymorphism show a reduced behavioral sensitivity to oral nicotine and tend to consume it in a different pattern when compared to wild-type monkeys. Thus the combination of highly homologous nAChR, higher cortical functions and capacity for complex training makes non-human primates a unique model to study in vivo functions of nicotinic receptors. In particular, primate studies on nicotine addiction and evaluation of therapies to prevent or overcome nicotine addiction are likely to be highly predictive of treatment outcomes in humans. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

SUBMITTER: Shorey-Kendrick LE

PROVIDER: S-EPMC4486519 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Nicotinic receptors in non-human primates: Analysis of genetic and functional conservation with humans.

Shorey-Kendrick Lyndsey E LE Ford Matthew M MM Allen Daicia C DC Kuryatov Alexander A Lindstrom Jon J Wilhelm Larry L Grant Kathleen A KA Spindel Eliot R ER

Neuropharmacology 20150207 Pt B

Nicotinic acetylcholine receptors (nAChRs) are highly conserved between humans and non-human primates. Conservation exists at the level of genomic structure, protein structure and epigenetics. Overall homology of nAChRs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. In addition to conservation at the protein level, there is high conservation of genomic structure ...[more]

PMID: 25661700

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Project description:Different protozoa and metazoa have been detected in great apes, monkeys and humans with possible interspecies exchanges. Some are either nonpathogenic or their detrimental effects on the host are not yet known. Others lead to serious diseases that can even be fatal. Their survey remains of great importance for public health and animal conservation. Fecal samples from gorillas (Gorilla gorilla) and humans living in same area in the Republic of Congo, chimpanzees (Pan troglodytes) from Senegal and one other from the Republic of Congo, Guinea baboons (Papio papio) from Senegal, hamadryas baboons (Papio hamadryas) from Djibouti and Barbary macaques (Macaca sylvanus) from Algeria, were collected. DNA was extracted and screened using specific qPCR assays for the presence of a large number of helminths and protozoa. Positive samples were then amplified in standard PCRs and sequenced when possible. Overall, infection rate was 36.5% in all non-human primates (NHPs) and 31.6% in humans. Great apes were more often infected (63.6%) than monkeys (7.3%). At least twelve parasite species, including ten nematodes and two protozoa were discovered in NHPs and five species, including four nematodes and a protozoan in humans. The prevalences of Giarida lamblia, Necator americanus, Enterobius vermicularis, Strongyloides stercoralis were similar between gorillas and human community co-habiting the same forest ecosystem in the Republic of Congo. In addition, human specific Mansonella perstans (5.1%) and other Mansonella spp. (5.1%) detected in these gorillas suggest a possible cross-species exchange. Low prevalence (2%) of Ascaris lumbricoides, Enterobius vermicularis, Strongyloides stercoralis were observed in chimpanzees, as well as a high prevalence of Abbreviata caucasica (57.1%), which should be considered carefully as this parasite can affect other NHPs, animals and humans. The Barbary macaques were less infected (7.2%) and Oesophagostomum muntiacum was the main parasite detected (5.8%). Finally, we report the presence of Pelodera sp. and an environmental Nematoda DNAs in chimpanzee feces, Nematoda sp. and Bodo sp. in gorillas, as well as DNA of uncharacterized Nematoda in apes and humans, but with a relatively lower prevalence in humans. Prevalence of extraintestinal parasites remains underestimated since feces are not the suitable sampling methods. Using non-invasive sampling (feces) we provide important information on helminths and protozoa that can infect African NHPs and human communities living around them. Public health and animal conservation authorities need to be aware of these infections, as parasites detected in African NHPs could affect both human and other animals' health.

Project description:Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mostly located in the post-synaptic membrane of cholinergic synapses. The natural neurotransmitter is acetylcholine, but they are also the direct targets for neonicotinoids, chemicals widely used against ectoparasites, arthropod vectors and agricultural pests. There are significant concerns regarding adverse effects of neonicotinoids on beneficial insects. In arthropods, functional nAChRs made of α subunits have been expressed from Drosophila genes, and hybrid receptors (sometimes also referred to as chimeric receptors) using species-specific α subunits and vertebrate β subunits have been expressed ex-vivo. Arthropod-specific nAChRs made of both α and β subunits from the target species have not been expressed ex-vivo. The aim of the current study was to express such receptors in Xenopus oocytes using only genes from Lepeophtheirus salmonis, to characterize them and study their modulation. Genes encoding α and β subunits of the nAChRs and three ancillary proteins, RIC-3, UNC-50 and UNC-74 were identified in the L. salmonis genome, subjected to RACE-PCR, cloned into an expression vector and the cRNA produced was then injected into Xenopus laevis oocytes. Co-expression of the ancillary proteins was essential for the successful expression of the L. salmonis nAChRs with both α and β subunits. Two functional nAChRs were identified: Lsa-nAChR1 consisting of α1, α2, β1 and β2 subunits, reconstituted to one distinct receptor, while Lsa-nAChR2, consisting of α3, β1 and β2 subunits reconstitutes receptors with two distinct characteristics. Out of seven neonicotinoids tested, six worked as partial agonist of Lsa-nAChR1 while only three did so for Lsa-nAChR2. Four non-neonicotinoid compounds tested had no effect on either of the nAChRs. The study demonstrated that fully functional, non-hybrid nAChRs containing both α and β subunits from an arthropod can be reconstituted ex-vivo by co-expression of essential ancillary proteins. Such models would be valuable for in-depth studies of effects by neonicotinoids and other compounds on target pests, as well as for studies of adverse effects on non-target arthropods.

Dataset Information

Nicotinic receptors in non-human primates: Analysis of genetic and functional conservation with humans.

Publications

Nicotinic receptors in non-human primates: Analysis of genetic and functional conservation with humans.

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