Tuesday, December 3, 2024
12/3/2024
Project Summary/Abstract The main goal of the lab is to provide detailed structural and functional insight into serotonin signaling and transport, and elucidate how drugs and medications modulate receptor and transporter function. Serotonin (5- hydroxytryptamine, 5-HT) regulates much of human physiology in- and outside the CNS, including cognition, mood, endocrine function and cardiovascular development. However, despite 5-HT's physiological and medical importance, atomic-level insight into the mechanisms of 5-HT signaling and transport, and how drugs interact with these molecular targets has remained incomplete. This lack of understanding has led to drug safety issues in the past, and greatly hindered the exploration of many 5-HT targets for novel therapeutic applications. Our lab thus focuses on three major directions to address these gaps. Firstly, we aim to investigate the molecular mechanisms by which 5-HT receptors signal through different transducers using structural and biochemical approaches. For instance, we will delineate the molecular determinants of how the 5-HT1A receptor signals via different G proteins of the Gi/o/z family, and elucidate how different drugs affect the receptor's conformational landscape to engage distinct signal transducers. A second major direction is to structurally and functionally characterize off-target activities of serotonergic drugs at understudied serotonin-related transporters such as the vesicular monoamine transporter 2 (VMAT2) or organic cation transporters (OCTs). Through these studies, we aim to provide a molecular level context of side effects reported for commonly prescribed drugs, but also to uncover the fundamental mechanistic properties of these understudied transporters. This work will further elucidate modulatory drug binding sites at these transporters and allow contrasting them with those found at 5- HT receptors. Lastly, we also aim to harness our structural and functional insights to develop target-selective and pathway-specific probes for both 5-HT receptors and transporters. The goal here is to generate chemically and pharmacologically novel and useful tools that enable inquiries into serotonin-related (patho)biology in vitro and in vivo. Our studies are both innovative technically and conceptually, as the unique combination of structural, pharmacological, and drug discovery approaches as well as the focus on both receptors and transporters will provide a holistic framework of serotonin-related biology and pharmacology at the molecular scale.
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