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They say imitation is the sincerest form of flattery. The field of optogenetics has taken that motto to heart and paid photosynthetic algae an immense complement. It’s actually very common for science and engineering technology to take a hint from nature, but in this case that hint was actually entire gene sequences.

Channelrhodopsins are a group of proteins found in some photosynthetic algae which directly regulate the flow of ions through membranes. I’ve talked about channel proteins before and how their activity can be modulated by either chemical or electrical signals, but these channelrhodopsins are special because they are activated by light.

The discovery of the genes that code for these proteins and the genetic engineering that has introduced these genes into mammalian cells has spurred research in the area called optogenetics. Perhaps most famously, optogenetics has been applied to neuroscience with the transfection of neurons with the channelrhodopsin gene. A neuron which has incorporated channelrhodopsin proteins into its cell membrane can be selectively activated simply by applying a specific wavelength of light. Using visible light to induce activation is far less invasive and offers much more control than direct electrical stimulation.

Scientists are studying all kinds of things using optogenetics, including Parkinson’s disease, narcolepsy, and depression but I want to focus on how light energy is transduced into an electrical signal inside a cell. The short and sweet version is that a molecule, retinal, changes shape when light hits it which in turn causes the channelrhodopsin protein to change shape. The new shape of the protein is said to be “open” and allows ions to enter the cell. If you want more of the juicy details, you’ll have to read on.

Although we talk about channelrhodopsin as responding to light, a molecule called retinal which binds to the channelrhodopsin protein is actually the light sensitive species. Retinal has two conformations; all-trans retinal has double bonds which form a straight chain while 13-cis retinal has one double bond that puts a kink in the chain. In the presence of the correct wavelength of light, in this case 470 nm, the molecule isomerizes from the straight-chain to the kinked conformation:

Image from “Channelrhodopsins,” Openoptogenetics: the optogenetics wiki powered by MediaWiki. Accessed here: http://www.openoptogenetics.org/index.php?title=Channelrhodopsins
 
How does this isomerization occur? It all has to do with the way light interacts with electrons in the molecule. You might remember that light is said to have energy and the amount of energy in a beam of light is defined by its wavelength. You might also know that electrons in a molecule exist at certain energy “levels” and adding energy to the molecule can promote electrons from their ground state energy to a higher energy state.

In all-trans retinal, the incidence of 470 nm light will excite an electron from its ground state to a higher state, breaking the straight-chain characteristic of the molecule. The result is free rotation of the last double bond in the molecule and the formation of a kink in the chain.

Now retinal isn’t just hanging around channelrhodopsin randomly. The molecule is positioned just so in the pore of the channel and it interacts with amino acid moieties, or chemical residues, in specific ways. Perhaps the most important interaction occurs between the oxygen atom at the end of the retinal molecule and an amino acid called lysine that is sticking into the pore of the channel. As you can see in the picture above, when all-trans retinal isomerizes to 13-cis retinal the position of the oxygen atom shifts, resulting in a shift in the lysine amino acid of the channel protein. You can imagine that there are many chemical interactions between and among amino acids in the protein itself, and if one piece of the puzzle moves—such as the lysine that is attached to retinal—the others shuffle a bit to maintain those favorable chemical interactions.

This process is so perfectly tuned that the tiny change in all-trans retinal due to light causes the pore in channelrhodopsin to open and allow ions through which then go on to produce a neural impulse in the cell. Think about how many doors this feat of nature and engineering has opened for neuroscientists! We can now excite very specific and even single neurons quickly, easily, and selectively. Optogenetics seems to be the holy grail of functional neuroscience studies, giving researchers unprecedented control over our most excitable cells. The future of optogenetics is bright—470 nm bright.



Sources and further reading:

Deisseroth, K. Controlling the Brain with Light. Scientific American, November 2010, pp 48-55.

Openoptogenetics: the optogenetics wiki. Channelrhodopsins: Background. http://www.openoptogenetics.org/index.php?title=Channelrhodopsins (Accessed Dec 14, 2013)

Watanabe, S. et al. Ultrafast endocytosis at mouse hipposcampal synapses. Nature, 2013, 504, 242-247.

Washington University in St. Louis, Undergraduate Biological Sciences program. I have seen the light! Vision and Light-induced Molecular Changes. http://www.chemistry.wustl.edu/~edudev/LabTutorials/Vision/Vision.html (Access Dec 14, 2013)

Background photo from: http://scitechdaily.com/optogenetics-allows-light-to-control-brains/
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