Scientists have discovered a molecular intermediate related to a serotonin receptor, which plays a role in conditions like depression and schizophrenia. This research presents a new potential target for drug development.
Misha Kudryshev’s laboratory at the Max Delbrück Center has found a molecular intermediate associated with a serotonin receptor implicated in illnesses such as depression and schizophrenia. Their findings, published in The EMBO Journal, suggest a new avenue for therapeutic approaches.
A recent study featured in “The EMBO Journal” reveals promising new options for treating psychiatric and gastrointestinal disorders that current medications struggle to address. Dr. Bianca Introini, along with her team from Professor Misha Kudryashev’s In Situ Structural Biology lab, have identified a stable intermediate of the pentameric serotonin-gated 5-HT3A receptor, a protein located in cellular membranes. Kudryashev notes that being able to pinpoint such a structure is remarkable, as it is typically very challenging to purify intermediates of membrane protein assembly. This intermediate could represent a novel target for drug intervention.
Serotonin is a well-established neurotransmitter that influences neural activities and various psychological functions. Medications that affect serotonin receptors are commonly used in psychiatry and neurology and are also prescribed to alleviate nausea and vomiting caused by chemotherapy and radiotherapy. However, these medications often bring about side effects that can limit their effectiveness.
Among the seven known serotonin receptors, 5-HT3A uniquely acts as an ion channel – these are transmembrane proteins that allow specific ions to flow across cell membranes. Cells containing 5HT3A ion channels are present in the brainstem and gastrointestinal tract. They play a crucial role in the digestive process, relay sensory information, and trigger the gag reflex.
Analyzing the structure of serotonin receptors
Cell membranes encase living cells. Many of these membranes harbor proteins that facilitate signal transmission and the movement of substances. Therefore, membrane proteins are vital for cell health, and any disruption in their function can lead to a range of diseases.
Multimeric membrane proteins consist of multiple copies of the same molecule that combine to form a functional structure. The construction and assembly of these proteins occur deep within cells, presenting challenges in studying the intermediates produced during this process.
For several years, the Kudryashev lab has been examining at an atomic level how the serotonin receptor ion channel opens and closes in response to serotonin binding. To analyze the protein structure, the research team employs cryo-electron microscopy, which enables imaging of a thin layer of frozen proteins or cells using electron beams.
Deviations from the expected five subunits
During the investigation of the 5-HT3A receptor structure, Dr. Introini discovered that some molecules were composed of four subunits forming a tetramer complex, instead of the expected five. “This was intriguing,” says Dr. Introini, “because Cys-loop receptors typically consist of five protein subunits.” Normally, five subunits come together to make a pentameric complex.
To gain a better understanding of the function of these tetramers, the team collaborated with researchers from The Research Center for Computer-aided Drug Discovery at the Institute of Biomedicine and Biotechnology in Shenzhen, China. Through computational simulations, they proposed that the tetramer serves as an intermediate form that transitions into the final pentameric structure.
Interestingly, the tetramers manifest in two different forms. One of these features a partially open extracellular domain, which, according to molecular dynamics simulation experiments, allows the insertion of the fifth subunit. Kudryashev clarifies this finding as evidence that the tetramer truly acts as an intermediate molecule.
“This publication not only enhances our understanding of the synthesis and assembly of these proteins and other similar multimeric proteins in membranes,” Kudryashev remarks, “but it also proposes an alternative method for regulating serotonin levels in cells by targeting this intermediate protein.”
