Some like it hot - receptors for capsaicin and wasabi

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Sandra Porter

To have an effect, a molecule must bind to a receptor and trigger a signal.  Studying a receptor's structure can give us insights about the way this triggering process works.

Capsaicin is a fascinating molecule that puts the "pep" into peppers.  Curiously, the amount of capsaicin in a pepper is measured with a test devised in 1912 by Wilbur Scoville.  Dried peppers are dissolved in alcohol, this liquid extract is diluted in water, and trained people determine the pepper's Scoville value by "tasting" the heat.

I wonder how these people are recruited.   I like hot sauce but I can't imagine being a Scoville chili tester, largely because of the chili's effects.

What do you feel when you eat chilis?

Heat?  Pain? Both?

What you feel results from a signal by the capsaicin receptor (TRPVI).  What can the structure of the capsaicin receptor tell us about its function?  Can we learn things from the capsaicin receptor that will help understand how other receptors work?  Like the wasabi receptor?

Let's find out.

capsaicin Capsaicin

 

 

 

 

 

 

 

 

 

 

 

 

 

Where does the capsaicin receptor hang out?

A good place to start is to figure out where the receptor is located in a cell.

We know some receptors are found in membranes, but others, like the estrogen receptor are located inside the cell.  Those kinds of receptors move into the nucleus and bind to DNA when they're target molecule enters the scene.

Other kinds of receptors stick through the cell membrane.

We can answer this question using Molecule World, a molecular modeling program for the iPad®, to color the TrpVI receptor model (3J5P) by charge.  We're only showing the core backbone of the protein below and hiding the amino acid side chains. That view lets us to see the secondary structure a bit more clearly.

capsaicin_charge

 

 

 

 

 

 

 

 

In the image above, you can see there are lots of helices on one side of the receptor and they're all colored grey.  A grey color is commonly used to represent neutral or uncharged residues.  If we color by hydrophobicity, we'll also learn these regions are hydrophobic.  That tells us this part of the receptor is stuck in the membrane.

But which end is outside the cell?  What do you think?  Is it the cup-shaped end, the flatter end, or is the structure turned sideways in the image above?

To answer this question, we need a little more help.

Capsaicin isn't the only thing that sends signals through this receptor, changes in pH, heat (~42°C), molecules like lysophosphatidic acid (LPA), and certain spider toxins, can affect signaling as well.

What does it feel like when you've been bitten by a spider?

Luckily, Liao et. al. (1) solved the structure of the capsaicin receptor in the presence of a spider toxin (3J5Q).  This spider toxin is a useful tool for us because it's a protein and can't go through the cell membrane.  This means we can use it to figure out which side of the receptor is inside the cell and which side is out.

In this image, I selected the spider toxin proteins and colored them by molecule.

You can see all four molecules of spider toxin are bound on the flat side of the receptor.  Since the grey region is in the membrane, the cup-shaped portion must be located inside the cell.

spider_capsaicin

 

 

 

 

 

 

 

 

 

And that's not all.

If we have both structures downloaded in Molecule World, we can compare the model of the TrpVI receptor alone to the model bound to spider toxin.

When we alternate between structures, it's almost like you see the channel open up.

image

 

 

 

 

 

 

 

 

What goes through the channel?

Since the structure is colored by charge, we can make some guesses about the kinds of ions that pass through the open channel.

 

What did this have to do with the wasabi receptor?

Now that you've experimented with the capsaicin receptor, you can apply what you've learned to a new structure that was solved just recently (2).  Use the PDB ID 3J9P to download the wasabi receptor in Molecule World from the PDB database.

You should be able to tell where the receptor is located in the cell, make a guess about which side is inside and which is out, and guess the kinds of ions that pass through the channel.

Have fun!

 

References

1. Liao M, Cao E, Julius D, Cheng Y. Structure of the trpv1 ion channel determined by electron cryo-microscopy.  Nature (2013) 504 p.107

2.  Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D.  Structure of the TRPA1 ion channel suggests regulatory mechanisms.  Nature. 2015 Apr 8. doi: 10.1038/nature14367. [Epub ahead of print]