Turn up the heat, flies still eat

A mystery has been unfolding at the intersection of pungent chemicals, temperate temperatures, and a question of detection: how do insects discriminate the noxious from the innocuous?  At the center is a single protein, TRPA1; however, this puzzle has implications from human pain to bug spray.

The subject of this story, TRPA1, is an ion channel gaining notoriety as an arbiter of agony.  From mollusks to mammals, TRPA1 is a biological irritant detector: it responds to pungent chemicals like those in mustard, wasabi, and garlic.  As we chop our onions and the tears flow, behind the scenes is TRPA1, gated by the reactive chemicals that waft into the air.  In fact, TRPA1 may lurk below the surface for many forms of irritation – the burn, the itch, the cough – and is implicated in maladies ranging from asthma, to inflammation, and pain.

In insects the story takes a twist, as TRPA1 mediates two senses.  On the one hand, TRPA1 in fruit flies and mosquitoes responds to the same chemicals that act on vertebrate orthologs.  In this role, TRPA1 stimulates gustatory neurons of the fly, detecting pungent chemicals and suppressing feeding before it is too late.

On the other hand, insect TRPA1 also responds to warmth.  Led by Brandeis University’s Paul Garrityour lab demonstrated previously that TRPA1 is essential for the fruit fly Drosophila melanogaster to select a comfortable temperature (~25C, ~77F).  Furthermore, our lab has demonstrated that TRPA1 is directly gated by warming (above ~27C, ~80F) acting as a molecular temperature sensor.

This brings us to the mystery: if Drosophila TRPA1 is activated by nasty chemicals and prevents flies from eating, and also gets activated by heating, how can a fly eat in the heat?

In a recent article published in the journal Nature, our lab reveals the mechanism.  We identified two isoforms (from alternate promoters) of Drosophila TRPA1.  The known isoform is gated by both pungent chemicals and warming.  However, we identified a new isoform that is selectively gated by chemicals. Check out Figure 1: neurons expressing the first isoform respond to both chemicals and temperature whereas neurons expressing the new isoform respond selectively to chemicals.

We also found that the temperature-insensitive form was expressed in the gustatory system of the fly, while the temperature-sensitive isoform is expressed inside the brain, so is shielded from chemicals.  In this way, the fly can eat in the heat because only a temperature-insensitive TRPA1 is modulating feeding.

The importance of distinguishing these two senses became clear when we mis-expressed the temperature sensitive isoform in aversive gustatory neurons.  When these engineered flies were gently warmed, they began to vomit uncontrollably, a dramatic demonstration of the behavioral imperative to distinguish noxious from innocuous stimuli.  Check out this video to see for yourself.

We then examined TRPA1 isoforms from malaria mosquitoes and found the same functional dichotomy observed in Drosophila.  This may explain how mosquitoes use a single channel to hunt for warm-bodied prey and avoid noxious repellents, and may provide two new targets for pest control: push on the chemical isoform to get bugs to leave you alone, or pull on the warmth-sensor to lure them to their death!

Beyond bug-sprays and bug-zappers, we have some tantalizing clues to how TRPA1 may further modulate its own temperature- and chemical-sensitivity.  The exact mechanisms are not clear but may have implications for the function of human TRPA1.  So, the mystery continues, but one thing is certain: TRPA1 promises to keep things spicy.

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