Deciphering the molecul ar pharmacology of the histamine H3 receptor
The histamine H3 receptor (H3R) is a G protein-coupled receptor predominantly expresse d in the central nervous system, where it regulates the release of hi stamine and other neurotransmitters involved in cognition, arousal, a nd sleep-wake regulation. Although H3R has been validated as a therap eutic target, the limited clinical success of H3R-directed drugs high lights the need for improved pharmacological tools and a deeper under standing of H3R signaling complexity. This thesis investigates H3R ph armacology through the development of novel photopharmacological tool s, analysis of ligand-biased signaling, and characterization of seven alternatively spliced H3R isoforms. Photopharmacological strategies were applied to create a light-activated H3R agonist, enabling spatio temporal 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, seve ral synthetic agonists and receptor isoforms preferentially recruit m ini-Gi protein while minimally engaging β-arrestin1 or β-arresti n2, as revealed by receptor-proximal biosensor assays. Together, thes e findings demonstrate that H3R signalling is shaped by ligand proper ties, optical control, and receptor isoforms, providing new tools and insights that may support the development of pathway-selective and i soform-aware strategies for targeting the H3R.
More information on the thesis
DESCRIPTION: The histamine H3 receptor (H3R) is a G protein-coupled re ceptor predominantly expressed in the central nervous system, where i t regulates the release of histamine and other neurotransmitters invo lved in cognition, arousal, and sleep-wake regulation. Although H3R h as been validated as a therapeutic target, the limited clinical succe ss of H3R-directed drugs highlights the need for improved pharmacolog ical tools and a deeper understanding of H3R signaling complexity. Th is thesis investigates H3R pharmacology through the development of no vel photopharmacological tools, analysis of ligand-biased signaling, and characterization of seven alternatively spliced H3R isoforms. Pho topharmacological 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 constitutiv e activity. In addition, several synthetic agonists and receptor isof orms preferentially recruit mini-Gi protein while minimally engagi ng β-arrestin1 or β-arrestin2, as revealed by receptor-proximal bio sensor assays. Together, these findings demonstrate that H3R signalli ng is shaped by ligand properties, optical control, and receptor isof orms, providing new tools and insights that may support the developme nt of pathway-selective and isoform-aware strategies for targeting th e H3R. More information on the thesis Deciphering the molecul ar pharmacology of the histamine H3 receptor END:VEVENT END:VCALENDAR