Saturday, March 30, 2013

Riskay Business? Receptors Specialized for Social Smells

Image from Wallrabenstein, et al., 2013

Linda Buck and Richard Axel transformed the study of smell with their Nobel Prize-winning discovery of the mammalian olfactory receptor (OR) genes in 1991. These genes code for a diverse set of cell-surface receptors expressed on the surface of sensory cells in the nose. Receptor diversity enables the detection of a broad array of odor molecules. With as many as 1,500 varieties, the OR gene family is the biggest in the human genome—testimony to the evolutionary importance of odor perception. OR genes create a type of receptor structure that elsewhere in the body figures in the detection of sex hormones and neurotransmitters.

In 2006, Stephen Liberles and Linda Buck found a second class of chemosensory receptors in the nose of humans, mice and fish. It consists of a handful of receptors (six to fifteen, depending on that species) that are structurally unrelated to ORs. Instead, they look like the receptors for biogenic amines, e.g., the neurotransmitters serotonin and dopamine. The new class was dubbed “trace amine-associated receptors” or TAARs because they are exquisitely sensitive to a specific class of molecule—volatile amines—that turns out to be common in mouse urine. Thereby hangs a tale.

Given the affinity of TAARs for the smelly amines in mouse piss, Liberles and Buck speculated that these receptors play a role in social behavior. This isn’t as crazy as it sounds—mice send all sorts of social messages via chemical cues in their urine. This January, Liberles and a team of colleagues advanced the story in much greater detail. They focused on one TAAR receptor which, in an odd resonance for perfume fans, is called TAAR5. It is especially sensitive at detecting trimethylamine (TMA), a molecule famous for having exactly the stink of rotting fish.

But for one enzyme, human urine would also smell of dead fish, since bacteria in our gut turn the choline in food into obnoxious TMA. Thankfully, almost everybody produces the flavin-containing monooxygenase 3 enzyme (FMO3), which chemically converts TMA to a non-smelly molecule. Those few unfortunates born with a defective FMO3 gene suffer from “fish odor syndrome,” and must modify their diet to avoid the stinky stigma.

Meanwhile, male mice have a ton of TMA in their urine while females have almost none. And while the odor of TMA at high levels is aversive to mice, it is attractive to both sexes at the concentrations found in urine. So what’s going on? Liberles et al. found that female mice produce the FMO3 enzyme which keeps TMA out of their pee. Males stop producing FMO3 at puberty and thus have TMA-stinky pee. Genetically controlled production of TMA, coupled with a preference for its odor, seems to occur only in the house mouse Mus musculus and not in other members of the genus Mus or other rodents such as rats. Liberles et al. speculate this synchronous evolution of odor biosynthesis plus behavioral response has something to do with signaling species identity. Research on a variety of rodents species is needed to see if the idea bears out.

In February, Thomas Bozza’s team at Northwestern used a variety of techniques to examine the functional sensory response of TAAR-expressing sensory cells. They conclude that TAARs “serve as high-affinity amine detectors in mammalian olfactory systems.” While TAARs are broadly tuned to detect amines, one in particular (TAAR4) is “exquisitely sensitive” to β-phenylethylamine—so much so that it rivals “the most sensitive mammalian chemosensory neurons yet examined.” And what is β-phenylethylamine? It’s a chemical found in the urine (and therefore scent marks) of carnivorous predators. Not a bad thing to be sensitive to if you’re a prey species like the mouse.

So what of the six human TAARs? Do these receptors make us exquisitely sensitive to TMA or β-phenylethylamine or other biologically relevant amines? Two TAARs are known to be expressed in the human nose. Bozza et al. expressed the human hTAAR5 gene in mouse sensory cells and found that it responds to N,N-dimethylethylamine and somewhat less to TMA.

Finally, also in February, a German team led by Ivonne Wallrabenstein expressed human hTAAR5 in animal cells and measured the receptor’s response to a wide variety of amines (pictured at the top of this post). The human TAAR5 receptor is highly and specifically sensitive to TMA and less so to dimethylethylamine (the two molecules in the shaded portion of the picture). You don’t have to be a specialist to get the gist of the results:

(The big response is TMA; the third response from the left is dimethylethylamine.)

Of what use is a specialized human ability to detect TMA? Wallrabenstein et al. note that besides being found in rotting fish, “TMA arises in rotting male ejaculate and vaginal secretions.” Yes, well . . . there’s that. But is TMA sensitivity simply an evolved reminder to wash after use? My hunch is that it’s more than that—possibly a means of detecting out-of-pair-bond copulation, or what in a less politically correct time we used to refer to as sneaky fucking.
Why u comin home 5 in the mornin
Somethins goin on, can I smell yo dick
                   --Riskay (2007)
Social smell signals, indeed.

The studies discussed here are “A second class of chemosensory receptors in the olfactory epithelium” by Stephen D. Liberles and Linda B. Buck, published in Nature 442:645-650, 2006; “Synchronous evolution of an odor biosynthesis pathway and behavioral response” by Qian Li, Wayne J. Korzan, David M. Ferrero, Rui B. Chang, Dheeraj S. Roy, Mélanie Buchi, Jamie K. Lemon, Angeldeep W. Kaur, Lisa Stowers, Markus Fendt, and Stephen D. Liberles, published in Current Biology 23:11-20, 2013; “Ultrasensitive detection of amines by a trace amine-associated receptor” by Jingji Zhang, Rodrigo Pacifico, Dillon Cawley, Paul Feinstein, and Thomas Bozza, published in Journal of Neuroscience 33:3228-3239, 2013; and “Human trace amine-associated receptor TAAR5 can be activated by trimethylamine,” by Ivonne Wallrabenstein, Jonas Kuklan, Lea Weber, Sandra Zborala, Markus Werner, Janine Altmüller, Christian Becker, Anna Schmidt, Hans Hatt, Thomas Hummel, and Günter Gisselmann, published in PLoS One 8:e54950, 2013.


Olfacta said...


Avery Gilbert said...



maxtonight said...

... Moreover, not a word about the obvious conclusion of death avoidance in the presence of these alarm trigger molecules. The obvious conclusion (which we have asserted for several years) is both a context and mechanism for several of the most ancient mysteries of the human experience. Beyond the laughable suggestion that these somehow evolved to detect rotting semen and vaginal secretions, these amines are omnipresent compounds of human decomposition and will be invariable present wherever remains are. This (conspecific death marker detection and associated avoidance behavior) is perhaps one of the most common survival strategies in nature and clearly, we do it too. When one also realizes the response to this exposure will be completely dependent on genotype (MAOA – L “Warrior” vs. non “L” variant), it explains why we observe two distinctly different responses in “Haunted” environments (Places where volatile con-specific bouquets are present). It also becomes clear why we have two camps that will never concede to the other because in all ways relevant, they live in two different sensory universes.