Deciphering the mole cular pharmacology of the histamine H3 receptor
The histam ine H3 receptor (H3R) is a G protein-coupled receptor predominantly e xpressed in the central nervous system, where it regulates the releas e of histamine and other neurotransmitters involved in cognition, aro usal, and sleep-wake regulation. Although H3R has been validated as a therapeutic target, the limited clinical success of H3R-directed dru gs highlights the need for improved pharmacological tools and a deepe r understanding of H3R signaling complexity. This thesis investigates H3R pharmacology through the development of novel photopharmacologic al tools, analysis of ligand-biased signaling, and characterization o f seven alternatively spliced H3R isoforms. Photopharmacological stra tegies were applied to create a light-activated H3R agonist, enabling spatiotemporal control of receptor activation. Pharmacological profi ling of human H3R isoforms revealed differences in ligand binding aff inities depending on their level of constitutive activity. In additio n, several synthetic agonists and receptor isoforms preferentially re cruit mini-Gi protein while minimally engaging β-arrestin1 or β- arrestin2, as revealed by receptor-proximal biosensor assays. Togethe r, these findings demonstrate that H3R signalling is shaped by ligand properties, optical control, and receptor isoforms, providing new to ols and insights that may support the development of pathway-selectiv e and isoform-aware strategies for targeting the H3R.
More info rmation on the thesis
DESCRIPTION: Deciphering the molecular pharmacology of the histamine H 3 receptor The histamine H3 receptor (H3R) is a G protein-coupled rec eptor predominantly expressed in the central nervous system, where it regulates the release of histamine and other neurotransmitters invol ved in cognition, arousal, and sleep-wake regulation. Although H3R ha s been validated as a therapeutic target, the limited clinical succes s of H3R-directed drugs highlights the need for improved pharmacologi cal tools and a deeper understanding of H3R signaling complexity. Thi s thesis investigates H3R pharmacology through the development of nov el photopharmacological tools, analysis of ligand-biased signaling, a nd characterization of seven alternatively spliced H3R isoforms. Phot opharmacological strategies were applied to create a light-activated H3R agonist, enabling spatiotemporal control of receptor activation. Pharmacological profiling of human H3R isoforms revealed differences in ligand binding affinities depending on their level of constitutive activity. In addition, several synthetic agonists and receptor isofo rms preferentially recruit mini-Gi protein while minimally engagin g β-arrestin1 or β-arrestin2, as revealed by receptor-proximal bios ensor assays. Together, these findings demonstrate that H3R signallin g is shaped by ligand properties, optical control, and receptor isofo rms, providing new tools and insights that may support the developmen t of pathway-selective and isoform-aware strategies for targeting the H3R.More information on the thesis END:VEVENT END:VCALENDAR