Structural and Functional Evolution of the Trace Amine-Associated Receptors TAAR3, TAAR4 and TAAR5 in Primates

Abstract

The family of trace amine-associated receptors (TAAR) comprises 9 mammalian TAAR subtypes, with intact gene and pseudogene numbers differing considerably even between closely related species. To date the best characterized subtype is TAAR1, which activates the Gs protein/adenylyl cyclase pathway upon stimulation by trace amines and psychoactive substances like MDMA or LSD. Recently, chemosensory function involving recognition of volatile amines was proposed for murine TAAR3, TAAR4 and TAAR5. Humans can smell volatile amines despite carrying open reading frame (ORF) disruptions in TAAR3 and TAAR4. Therefore, we set out to study the functional and structural evolution of these genes with a special focus on primates. Functional analyses showed that ligands activating the murine TAAR3, TAAR4 and TAAR5 do not activate intact primate and mammalian orthologs, although they evolve under purifying selection and hence must be functional. We also find little evidence for positive selection that could explain the functional differences between mouse and other mammals. Our findings rather suggest that the previously identified volatile amine TAAR3–5 agonists reflect the high agonist promiscuity of TAAR, and that the ligands driving purifying selection of these TAAR in mouse and other mammals still await discovery. More generally, our study points out how analyses in an evolutionary context can help to interpret functional data generated in single species.

Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

“…While all TAAR sequences do cluster together, the relationships among TAAR subtypes are highly dynamic, reflecting the extensive expansion and contraction events characterizing this receptor family's evolution (Lindemann et al, 2005;Hashiguchi and Nishida, 2007;Stäubert et al, 2010Stäubert et al, , 2013. In fact, the TAAR subtree, displayed in Figure 5, differs somewhat from previously proposed TAAR phylogenies (Lindemann et al, 2005;Hashiguchi and Nishida, 2007).…”

Evolution of GPCR: Change and continuity

“…Eventually, products of this process can be identified in the genome as pseudogenes in which the ancestral gene can still be recognized but nonsense or frame shift mutations are unambiguous signs of functional inactivation. In the case of TAAR, phylogenetic estimates suggest that accumulation of such obvious features takes roughly 7-10 Myr of neutral evolution [80]. However, missense mutations that impair protein function may render a gene functionally inactive although there is none of the critical pseudogene features present.…”

Determinants involved in subtype‐specific functions of rat trace amine‐associated receptors 1 and 4

“…However, little is known about the other Taar subtypes probably because of difficulties in their experimental testing. For example, the TA1 agonists b-PEA and tryptamine are very low efficient agonists activating mouse and rat Taar4 orthologs through the Gasprotein/AC pathway (Borowsky et al, 2001;Liberles and Buck, 2006;Staubert et al, 2010). These different pharmacological properties may be caused by structural differences between the two Taar subtypes.…”

“…As shown recently, activation of Taar3-5 by volatile amines is also highly species-specific, and there is no evolutionary evidence that volatile amines are the Taar agonists nature selected for (Staubert et al, 2010). Mouse and rat Taar4 were found to be sensitive to degradation products of classical biogenic amines, namely b-PEA, bmethylphenylethylamine and tryptamine, as well as to the imidazoline derivatives naphazoline and xylometazoline and shown to signal via the Gas-protein/AC pathway (Borowsky et al, 2001; Liberles and Buck, 2006;Staubert et al, 2010). In humans and many primates, TAAR4 is a pseudogene (Staubert et al, 2010).…”

“…Mouse and rat Taar4 were found to be sensitive to degradation products of classical biogenic amines, namely b-PEA, bmethylphenylethylamine and tryptamine, as well as to the imidazoline derivatives naphazoline and xylometazoline and shown to signal via the Gas-protein/AC pathway (Borowsky et al, 2001; Liberles and Buck, 2006;Staubert et al, 2010). In humans and many primates, TAAR4 is a pseudogene (Staubert et al, 2010). Furthermore, many previous studies identified significant differences in plasma membrane expression of Taar in heterologous cell systems (Borowsky et al, 2001;Bunzow et al, 2001;Miller et al, 2005;Lindemann and Hoener, 2005b;Grandy, 2007;Wainscott et al, 2007;Wolinsky et al, 2007;Barak et al, 2008;).…”