Studying signalling paradigms and regulation of the muscarinic acetylcholine receptor M5 using dualsteric and photoswitchable ligands

• Applicant: Dr. Sophie Anna Maria Steinmüller
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538291523

My application for the Walter-Benjamin-Fellowship is centred around the muscarinic acetylcholine receptor M5 (M5R), which is implicated in a spectrum of diseases associated with cholinergic dysregulation, including Alzheimer’s disease, schizophrenia and even drug addiction. The M5 subtype is a leading candidate for therapeutic development and is the least abundant yet most selectively expressed subtype of the muscarinic receptor family, therefore minimizing off-target effects. Despite its promising potential, the M5R has been mostly overlooked, which is due to an absence of selective pharmacological tools and a gap in knowledge concerning its downstream signalling and regulation. My aim is to fill this knowledge gap by developing novel ligands, which selectively target the M5R. As a first step, I will identify these ligands from a set of compounds targeting both the allosteric and orthosteric site of M5R, by evaluating efficacy and subtype selectivity. These ligands will then be used to unravel how signalling, desensitisation and downregulation of M5R are controlled. Investigations into these mechanisms will use established biochemical readouts of activity and biosensors as well as confocal microscopy to elucidate how signalling is initiated, influenced and regulated. Therefore, specific molecular effectors and mechanisms will be identified and analysed with regard to signalling outcome (i. e. transcriptional response). Furthermore, photoswitchable ligands will be applied to control signalling of M5R in a spatiotemporal manner which will enable identification of novel signalling paradigms at different cellular locations. These findings will significantly contribute to our understanding of this understudied receptor, its specific functional roles, and will eventually enable the development of therapeutic strategies for addiction and neuropsychiatric disorders as well as other conditions associated with dysregulated M5R function.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Dr. James Hislop, Ph.D.