Pheromone puzzle

A couple of weeks ago I attended a presentation given by Lisa Stowers from Scripps, entitled “Decision-making in the nose: a molecular rationale for the unpredictable nature of female behavior”. The catchy title did its job, so I was there, learning that reaction of female mice on male pheromones depends on (suprise-surprise!) phase of their estrous cycle. The neurobiology behind it is quite amazing, definitely worth reading about. However, my interest was triggered by one question asked after the presentation.

First, a brief introduction. Pheromone communication between mice partially occurs via major urinary proteins (MUPs). These proteins are produced by many mammals but not by humans. In mice, secretion of particular MUPs causes corresponding behavioral reaction of other mice (e.g., aggression in males or attraction/indifference in females). There are MUPs-specific neurons in mouse nose that regulate pheromone-driven behavior. The question that intrigued me the most was ‘how do MUPs get into the nose?’

These proteins, although small – 19 kDa – are not at all volatile. But mice don’t have to stick their noses into each other’s urine for sensing them. And recombinant purified MUPs work as well as the native ones. In the same way cats’ MUPs are responsible for allergic reaction in some people. How do they get into the blood? No one needs to sniff or lick a cat for that, yet the effect is so powerful.

Turns out that nobody knows for sure how it works. Yes, MUPs have binding pockets for smaller pheromones, which are secreted with urine. But it doesn’t explain how recombinant MUPs, produced in bacteria and never exposed to the urine, cause similar behavioral changes. Yet MUPs do activate G protein-dependent pathways, different from small molecules they could release.

A recent review suggests the following mechanism for sensing darcin, a potent mouse peptide pheromone:

Volatiles in the urine marks attract female mice […]. As their nostrils touch the urine marks, molecules of darcin are sniffed into the VNO, which pumps them into the sensory zone of the VNO [Vomeronasal organ].

Although one can buy this explanation for darcin in particular, it doesn’t explain MUPs-driven effects emerging without close physical contact. How many protein molecules can a person, who is allergic to cats, sniff before having the nose running? If the mechanism is the same as for darcin, and some protein molecules could get into nose for instance on dust particles, this could be actually the most potent molecular recognition process available for humans!

 

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Author: Slava Bernat

I did my PhD in medicinal chemistry/chemical biology of G protein-coupled receptors and then explored some chemical biology of non-coding RNA as a postdoc. Currently I'm working in a small biotech company in San-Francisco Bay area as a research chemist. I'm writing about science, which catches my attention in rss feed reader and some random thoughts or tutorials.

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