Acetylcholine receptors, structures on the membranes of nerve and muscle cells, act as gateways for the passage of chemical signals. The first high-resolution image of the functional part of these receptors hints at the significance of two common molecules—water and sugar—in its activity. The researchers who created the image also performed tests that confirm the role of the two molecules.
The docking of acetylcholine triggers a change of shape within its receptor that creates a passage allowing a flood of ions through the membrane. Those ions can spur responses in other neurons or in muscle cells.
The new image shows a chain of sugar molecules—known to be part of the acetylcholine receptor but previously considered unimportant—located near the receptor’s opening. The sugar chain seems to act as a hinge on the gate of the receptor, a role that “could have a significant impact on the quickness of the signal,” says lead author Cosma Dellisanti of the University of Southern California in Los Angeles.
One of the main effects of nicotine is to trigger acetylcholine receptors. Separately, impaired receptors have been linked to Alzheimer’s disease and Parkinson’s disease. The new findings may help scientists design drugs that target addictions, the brain diseases, and other ailments, says Dellisanti.
To get a high-resolution picture, Dellisanti and his colleagues first painstakingly crystallized the proteins that make up the functional part of the receptor. By analyzing how X rays scattered off the crystals, the researchers deduced the arrangement of atoms within them. As well as locating the sugar molecules, the team found a pocket of water molecules in the core of the receptor—a surprising discovery because the internal structure of membrane proteins is typically assumed to be hydrophobic, or water-repellent.
The close association of sugar and water molecules led the researchers to suspect that both play a role in the receptor’s function, Dellisanti says. To test this hypothesis, researchers removed the sugar chain and found that the truncated receptor failed to open properly.
The team then engineered the receptor to ensure its interior would be hydrophobic, interfering with the function of the water molecules. Again, the change impaired the receptor’s activity.
Finally, simultaneously disrupting the roles of both the sugar and water molecules rendered the receptor useless. “These two elements are fundamental for the protein to work and were never considered before,” Dellisanti says.
The scientists suggest that water acts as a lubricant for the shape-changing sugar hinge as the receptor opens. Their results appear online in the August Nature Neuroscience.
The mechanism of the receptor is extremely complex, with hundreds of molecular interactions, says Anthony Auerbach of the State University of New York at Buffalo. “Now we also have to think about attached sugars and buried water molecules as being part of the chemical reaction.”
While Auerbach notes that this study provides only a snapshot of the receptor’s action, he says that the work “brings us closer to understanding how the acetylcholine receptor changes its shape and how drugs alter the function.”