Antidepressants are used to treat depression as well as other health conditions, such as anxiety, pain, and insomnia. Some of the most common antidepressants are called selective serotonin reuptake inhibitors (SSRIs). These work by increasing the amount of available serotonin, a chemical messenger that helps brain cells, or neurons, communicate. Serotonin levels affect sleep, mood, cognition, pain, hunger, and even aggressive behaviors.
After being released into the gaps between neurons, serotonin is pumped back for reuse into the cell that released it via the serotonin transporter protein. SSRIs slow this recycling process by blocking the pump, leaving the serotonin accessible to other neurons.
A research team led by Dr. Eric Gouaux of Oregon Health and Science University set out to solve the structure of the human serotonin transporter and determine how SSRIs interact with it. The research was funded in part by NIH’s National Institute of Mental Health (NIMH).
The serotonin transporter can be difficult to prepare for X-ray crystallography, a technique that creates an image of a protein’s 3-D structure. The protein is normally unstable during the purification and crystallization processes. The researchers genetically altered the transporter to withstand the temperatures used for isolation. They also added small antibody fragments to the protein solution to encourage crystallization. Using these modifications, they were able to create small crystals suitable for X-ray crystallography.
The technique yielded a detailed molecular map of the human serotonin transporter’s structure. The scientists were able to identify where different molecules interact with the transporter, including the sodium and chloride ions that are necessary for pumping serotonin.
The group next determined where 2 SSRIs, citalopram (CeleXA) and paroxetine (Paxil), take hold of the transporter. They found that both bind to the pump’s primary central binding site, preventing serotonin from binding and being pumped into the neuron. The SSRIs also fit in a second site on the protein, called an “allosteric” site, which affects how quickly molecules can get out of the central pocket. Thus, compounds that bind to this allosteric site can affect transport activity as well.
The researchers could also see where genetic variations associated with various psychiatric disorders are located in the transporter. Knowing the structure of the transporter can help researchers gain insights into the molecular causes of these disorders and of antidepressant treatment resistance.
“The heavy toll that devastating illnesses like anxiety and depression have on families and communities is, in many ways, incalculable,” says Gouaux. “Revealing the precise structure of the serotonin transporter holds promise for the development of life-changing drug treatments for these diseases.”