Analysis of the conformational cycle of the human serotonin

Membrane proteins from the so-called solute carrier (SLC) family play a key role in the human body. They are responsible for transporting water-soluble substances across cell membranesa process essential for maintaining metabolism. More than 100 SLC genes have been linked to human diseases, which is why there is an urgent need to develop new treatments and drugs. However, we still lack a basic understanding of how many of these SLC proteins actually work. One reason is that their activity depends on conditions like temperature or the distribution of ions, which are difficult to study in detail. This project focuses on one specific SLC protein: the serotonin transporter, also known as SERT. In the first part of the project, we will investigate how changes in temperatureespecially at body temperature (37 C)affect the different steps in SERTs transport cycle. Using experimental data, we will develop a detailed kinetic model to describe how temperature influences the transport process. The second part of the project explores how certain substances, called allosteric modulators, affect SERT function. The main question here is: at which stage in the transport process do these modulators act? To answer these questions, we will use a special measurement method called the patch-clamp technique. This allows us to study the activity of SERT under very controlled conditionsincluding temperature. The data we collect will be analyzed using mathematical models. This helps us understand exactly how fast each step in the transport process happens, and how these steps are controlled. A key innovation in this project is the systematic investigation of how body temperature affects SERT functionsomething that has mostly only been studied at room temperature until now. By combining experiments with modeling, we aim to build a detailed energy landscape model of the transport process. This knowledge is crucial for understanding how drugs can specifically interfere with SERTa vital step toward developing new therapies for diseases linked to this transporter.