Imandra Kempe (PhD-student)
Biased signaling in homo- and heterodimeric serotonin receptors – from structural biochemistry to systemic neuroscience
Nearly 40% of the population in Europe suffers from neuropsychiatric diseases including amongst others depression, anxiety disorders or schizophrenia. To date, various antipsychotic drugs are available, which either reduce or even block the occurrence of most of the according symptoms. However, the majority of pharmacological treatment is accompanied by various adverse effects such as drowsiness, dizziness, nausea or in some cases even more severe effects like seizures. Moreover, a significant number of patients remains pharmacoresistant and does not respond to any medication.
In this context, a lot of current research is focusing on G-protein coupled receptors (GPCRs), which are the main target of most of the antipsychotic drugs. Previously, it was assumed, that upon binding of specific ligands the activation of GPCRs is based on an “on- and off-” mechanism, which leads either to the inhibition or activation of signal transmission. Recent studies, however, demonstrate that different agonist ligands may affect GPCRs differently and that GPCRs are able to form homo- or heterodimers, which enable the receptors to interact with each other and in this way to alter the signaling cascade. Different mechanisms of “biased signaling” are of high interest for antipsychotic drug research. By understanding the underlying processes of “biased-signaling” in GPCRs, drugs can be designed that activate particular pathways differentially.
This PhD project is done in close cooperation with Prof. Dr. Olivia Masseck and Dr. Mario Waespy and is focusing on “biased-signaling” in homo- and heterodimeric serotonin (5-HT) receptors. In particular, the interaction between the 5-HT1A and the 5-HT2C receptors, which play a major role in depression, will be investigated. The aim will be implemented performing biochemical, cell biological and behavioral experiments:
- Biochemistry: the biochemical dynamics of 5-HT1A and 5-HT2C receptors after interaction with different agonists will be simulated and their functions, mechanisms and interactions will be characterized
- Cell culture: 5-HT1A and 5-HT2C receptors will be co-transfected into HEK-293 cell lines, on which calcium imaging, FRET and FLIM measurements will be performed, in order to prove heterodimerization and interactions.
- Behavioral paradigm: Behavioral effects of different 5-HT1A and 5-HT2C receptor agonists (or antagonists) in rodents will be assessed using appropriate paradigms (e.g. prepulse inhibition of startle).