In a study published this week in Nature, researchers have used high-powered microscopes to view serotonin activating its receptor for the first time. The images reveal molecular details about the receptor that could improve drug design to treat a multitude of diseases.
Serotonin receptors sit in cell membranes throughout the body, including the brain, stomach, and the associated nervous system. Drugs that inhibit serotonin receptors help control post-operative nausea, support cancer therapies, and treat gastrointestinal conditions like irritable bowel syndrome. These inhibitors are also used as anti-depressants and promote attention and memory.
Broad application of serotonin inhibitors comes with side effects, in part due to suboptimal drug-receptor interactions. "Successful design of safer therapeutics has been slowed because there is a limited understanding of the structure of the serotonin receptor itself, and what happens after serotonin binds to it,” says Sudha Chakrapani, Ph.D., of Case Western Reserve University School of Medicine. “Our work is the first to describe how serotonin activates the full-length serotonin receptor at a level of detail to nearly the individual atom."
Chakrapani's team captured images that showed serotonin attaching to its receptor and twisting open the channel. The researchers then analyzed simulations of the movement of sodium molecules through the newly opened channels, highlighting distinct conformations of the serotonin receptor that would make a cell more or less permeable to certain molecules. It also shows which portions of the receptor are most critical for proper channel function.
The entire interaction stretches about a few billionths of a meter across. Microscopes have only recently evolved to capture such tiny molecules. Cutting-edge technology in the new study—cryo-electron microscopy—earned a 2017 Nobel Prize in chemistry. It uses high-powered microscopes to take snapshots of proteins in action, and compiles them into three-dimensional structural models.
The researchers hope their findings could lead to the development of more precise drugs that target specific regions or functions of serotonin receptors. "It's likely that new and different drugs can work as effective serotonin inhibitors, especially if they're designed to work differently than current drugs," says first author Sandip Basak, Ph.D. "We're actively pursuing these approaches to help design safer therapeutics that modulate the serotonin receptor to treat a range of conditions."
Image: Serotonin-induced activation of serotonin (3A) receptors. Image courtesy of Case Western Reserve University School of Medicine.