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 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.

Massive expansion and diversity of nicotinic acetylcholine receptors in lophotrochozoans

“…The massive expansion has resulted in high sequence diversity of the expanded nAChR genes. In C. gigas , protein length of nAChRs varied greatly from 66 to 2013 aa, compared with 458 to 627 aa in humans [34]. Among the 141 LBD domains found in C. gigas , eight did not have the Cys-loop, which was critical for the function of the ligand-gated ion channel.…”

E-cigarette vape and lung ACE2 expression: Implications for coronavirus vulnerability

“…A variety of nAChR subunits have been documented within the lungs in humans ( Lam et al, 2007 , 2016 ), non-human primates ( Shorey-Kendrick et al, 2015 ) and rodents ( Grau et al, 2007 ). In the current studies, we examined expression of α5 and α7 nAChR subunits.…”

Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution

“…Only one polymorphism in the CHRNA5 gene associated with tobacco dependence in humans has been preclinically studied: the non-synonymous SNP rs16969968 (hereafter called α5SNP in the context of preclinical modelling). First, a recent study took advantage of the facts that cynomolgus monkeys naturally express the α5SNP at a frequency similar to humans and that there is great homology of nAChR protein sequences between human and non-human primates (98%) (Shorey-Kendrick et al, 2015). WT (n=5) and α5SNP cynomolgus monkeys (n=2) had a choice to drink at a bottle containing a nicotine solution with sweetener or at a bottle containing water, and the concentration of nicotine was progressively increased over time (from 25 to 750 µg/ml; 6 days per concentration).…”