Coleman, James L J (2018) The pharmacology and physiology of orphan G protein-coupled receptor, GPR37L1. PhD thesis, Victor Chang Cardiac Research Institute, St Vincent's Clinical School, Faculty of Medicine, UNSW.
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James Coleman 2018 PhD Thesis VCCRI UNSW.pdf Download (15MB) | Preview |
Abstract
G protein-coupled receptors (GPCRs) are integral membrane proteins, exquisitely evolved to allow the eukaryotic cell to detect and respond to ligands - discrete extracellular stimuli, commonly small molecules or peptides. The ~800 GPCRs in the human genome are not only fundamental to our physiology, but comprise a wealth of pharmacological targets in the treatment of disease. However, approximately 100 GPCRs are yet to be matched with endogenous ligands, and are termed orphans. One such orphan, GPR37L1, was previously linked to blood pressure regulation, suggesting the pharmacological targeting of this receptor may represent a new strategy in the treatment of hypertension – a disease that is often refractory to existing treatments. Unfortunately, this previous finding was superficially assessed, and the cardiovascular effects of GPR37L1 remained unconfirmed. Further, fragments of the GPR37L1 N-terminus have been identified in human spinal fluid, suggesting the receptor undergoes novel post-translational modification. Accordingly, I tested two main hypotheses in this thesis: that GPR37L1 (i.) undergoes, and is regulated by, N-terminal proteolysis and (ii.) contributes to cardiovascular control. Using in vitro and ex vivo approaches, I report that GPR37L1 signals through the Gαs G protein in absence of ligand, and is subject to metalloprotease-mediated N-terminal truncation, which abrogates this activity. I next defined the receptor’s expression profile, using mouse tissue, and observed that expression of GPR37L1 was restricted to the central nervous system (CNS). I then investigated the cardiovascular phenotype of mice lacking GPR37L1 (GPR37L1KO/KO), compared to wild-type controls, and discovered intriguing sex differences. Blood pressure was increased in female, but not male, GPR37L1KO/KO mice. However, when challenged with an angiotensin II infusion, only male GPR37L1KO/KO mice developed a heart failure-like phenotype. The experiments herein show GPR37L1 to be regulated by a novel metalloprotease-dependent mechanism, and that the receptor contributes to cardiovascular regulation in a sexually-dimorphic manner. Further, the CNS-restricted expression of GPR37L1 suggests it to be a hitherto unknown contributor to central cardiovascular control.
| Item Type: | Thesis (PhD ) |
|---|---|
| Keywords: | SUPERVISORS: Assoc/ Prof Nicola Smith, Prof Bob Graham |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 21 Jan 2019 04:06 |
| Last Modified: | 21 Jan 2019 04:06 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/790 |
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