Nicotinic receptors in non-human primates

Analysis of genetic and functional conservation with humans

Lyndsey E. Shorey-Kendrick, Matthew Ford, Daicia C. Allen, Alexander Kuryatov, Jon Lindstrom, Larry Wilhelm, Kathleen (Kathy) Grant, Eliot Spindel

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    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 α5 nAChR Asp398Asn polymorphism to the human α5 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 α5 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'.

    Original languageEnglish (US)
    Article number5737
    Pages (from-to)263-273
    Number of pages11
    JournalNeuropharmacology
    Volume96
    Issue numberPB
    DOIs
    StatePublished - Jun 27 2015

    Fingerprint

    Nicotinic Receptors
    Nicotine
    Primates
    Macaca fascicularis
    Macaca
    Epigenomics
    Haplorhini
    Single Nucleotide Polymorphism
    Proteins
    Introns
    Cognition
    Molecular Biology
    Exons
    Rodentia
    Smoking
    Ligands

    Keywords

    • Cynomolgus
    • Macaque
    • Nicotine
    • Nicotinic receptor
    • Non-human primate
    • Rhesus

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience
    • Pharmacology

    Cite this

    Nicotinic receptors in non-human primates : Analysis of genetic and functional conservation with humans. / Shorey-Kendrick, Lyndsey E.; Ford, Matthew; Allen, Daicia C.; Kuryatov, Alexander; Lindstrom, Jon; Wilhelm, Larry; Grant, Kathleen (Kathy); Spindel, Eliot.

    In: Neuropharmacology, Vol. 96, No. PB, 5737, 27.06.2015, p. 263-273.

    Research output: Contribution to journalArticle

    Shorey-Kendrick, Lyndsey E. ; Ford, Matthew ; Allen, Daicia C. ; Kuryatov, Alexander ; Lindstrom, Jon ; Wilhelm, Larry ; Grant, Kathleen (Kathy) ; Spindel, Eliot. / Nicotinic receptors in non-human primates : Analysis of genetic and functional conservation with humans. In: Neuropharmacology. 2015 ; Vol. 96, No. PB. pp. 263-273.
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    AU - Shorey-Kendrick, Lyndsey E.

    AU - Ford, Matthew

    AU - Allen, Daicia C.

    AU - Kuryatov, Alexander

    AU - Lindstrom, Jon

    AU - Wilhelm, Larry

    AU - Grant, Kathleen (Kathy)

    AU - Spindel, Eliot

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    N2 - 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 α5 nAChR Asp398Asn polymorphism to the human α5 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 α5 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'.

    AB - 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 α5 nAChR Asp398Asn polymorphism to the human α5 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 α5 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'.

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