Anatomy and Neuroscience - Theses
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ItemCommitment to Serotonergic Signalling: Evolution and Distribution of the Serotonin Receptors( 2022)Serotonin is a subclass of neurotransmitters and a relatively simple metabolite. The serotonin system underpins a multitude of biological functions by coupling with diverse serotonergic signalling. The effectors of serotonergic signalling are the serotonin receptors: a family of GPCRs (G protein-coupled receptors). These receptors are associated with diverse biological functions and are the primary sites of action for many psychotherapeutic drugs. We describe what commitment to serotonergic signalling entails by quantifying the diversity of this family in terms of receptor sequences, and expression patterns in the brain and systemic tissues. Sampling receptor sequences from the HTR (serotonin receptors) family, we constructed an updated phylogeny. We interpolated Bayesian priors to include key evolutionary events and to date the evolution of the family. Using RNA sequencing data, we provide the first systematic evaluation of the HTR distribution in the human body and organised the family based on their shared expression patterns. The phylogeny recapitulated early radiation of HTRs predating vertebrate evolution and demonstrated the three present clades of Galphas-coupled HTRs lack a singular ancestral node. The RNA-sequence analysis identified the systemic as well as brain-specific receptors, and reproducibly detected ten family members in the brain, which could be sub-classified by their co-expression patterns in cortical and subcortical regions. Together, the phylogenetic tree and the transcriptome map underscore the diversity of the HTR family, with multiple members evolved to activate all types of Galpha pathways specifically in the brain as well as systemically. Thus, through applying ‘omics data, the thesis outputs present the first systematic description of the family. The findings of this thesis reinforce the fact that multiple serotonin receptors are not evolutionary redundancies, but rather each receptor corresponds to specialised tissue distribution. An accurate understanding of the commonalities and contrasts among the subtypes would aid the development of subtype-specific drug targets.