The role of G protein alpha 11 in calcium and glucose homeostasis
<p>Guanine nucleotide-binding (G) proteins act as molecular switches to transduce stimuli received by G protein-coupled receptors (GPCRs) into intracellular responses. For example, Gα11 mediates signalling by the calcium-sensing receptor (CaSR), a class C GPCR, to regulate calcium homeostasis....
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2020
|
| Subjects: |
| _version_ | 1797111329286258688 |
|---|---|
| author | Glück, AK |
| author2 | Thakker, RV |
| author_facet | Thakker, RV Glück, AK |
| author_sort | Glück, AK |
| collection | OXFORD |
| description | <p>Guanine nucleotide-binding (G) proteins act as molecular switches to transduce stimuli received by G protein-coupled receptors (GPCRs) into intracellular responses. For example, Gα11 mediates signalling by the calcium-sensing receptor (CaSR), a class C GPCR, to regulate calcium homeostasis. Germline CaSR and Gα11 inactivating and activating mutations cause calcitropic disorders such as familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH) types-1 and -2, respectively. In addition, non-calcitropic disorders may also occur, e.g. Nuf mice (model for ADH1) have impaired glucose metabolism. This thesis aims to: identify and characterise rare Gα11 variants from online databases; investigate glucose metabolism of Dsk7 mice (model for ADH2); study CaSR signalling differences between Gα<sub>11</sub> and the closely related Gα<sub>q</sub>; and explore CaSR functional selectivity and G protein biased signalling. My analysis revealed novel Gα11 variants that cause CaSR signalling abnormalities in vitro and are associated with hypercalcaemia in patients. Moreover, some Gα11 variants also disrupted signalling by prototypical class A GPCRs and promoted biased and promiscuous signalling. In contrast, Gα<sub>11</sub> gain-of-function did not impair glucose homeostasis or pancreatic islet architecture in Dsk7 mice, indicating that other G proteins may be involved in these non-calcitropic CaSR functions. Gαq mutations were not found in patients with FHH or ADH, and engineering FHH2- and ADH2-associated Gα11 mutations in Gαq did not alter Gα<sub>q</sub> function, thereby highlighting functional differences between them. Analysis of CaSR functional selectivity showed that the CaSR is a promiscuous receptor which activates eight G proteins and that clinically approved CaSR allosteric modulators can promote biased signalling. In summary, my thesis illustrates the importance of Gα<sub>11</sub> for CaSR signalling, demonstrated by identification of additional FHH2 mutants, and that Gα11 mutations disrupt signalling by other GPCRs, thereby possibly leading to wider effects. Additionally, CaSR biased-signalling highlights the importance of G proteins other than Gα11 for this GPCR.</p> |
| first_indexed | 2024-03-07T08:07:15Z |
| format | Thesis |
| id | oxford-uuid:d847aa8e-9d64-48e1-b912-75fdd6dc8ecd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:07:15Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:d847aa8e-9d64-48e1-b912-75fdd6dc8ecd2023-11-06T09:22:03ZThe role of G protein alpha 11 in calcium and glucose homeostasisThesishttp://purl.org/coar/resource_type/c_db06uuid:d847aa8e-9d64-48e1-b912-75fdd6dc8ecdGeneticsMetabolismEndocrinologyCell signallingEnglishHyrax Deposit2020Glück, AKThakker, RVLines, KERussell, RGCChatterjee, VK<p>Guanine nucleotide-binding (G) proteins act as molecular switches to transduce stimuli received by G protein-coupled receptors (GPCRs) into intracellular responses. For example, Gα11 mediates signalling by the calcium-sensing receptor (CaSR), a class C GPCR, to regulate calcium homeostasis. Germline CaSR and Gα11 inactivating and activating mutations cause calcitropic disorders such as familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH) types-1 and -2, respectively. In addition, non-calcitropic disorders may also occur, e.g. Nuf mice (model for ADH1) have impaired glucose metabolism. This thesis aims to: identify and characterise rare Gα11 variants from online databases; investigate glucose metabolism of Dsk7 mice (model for ADH2); study CaSR signalling differences between Gα<sub>11</sub> and the closely related Gα<sub>q</sub>; and explore CaSR functional selectivity and G protein biased signalling. My analysis revealed novel Gα11 variants that cause CaSR signalling abnormalities in vitro and are associated with hypercalcaemia in patients. Moreover, some Gα11 variants also disrupted signalling by prototypical class A GPCRs and promoted biased and promiscuous signalling. In contrast, Gα<sub>11</sub> gain-of-function did not impair glucose homeostasis or pancreatic islet architecture in Dsk7 mice, indicating that other G proteins may be involved in these non-calcitropic CaSR functions. Gαq mutations were not found in patients with FHH or ADH, and engineering FHH2- and ADH2-associated Gα11 mutations in Gαq did not alter Gα<sub>q</sub> function, thereby highlighting functional differences between them. Analysis of CaSR functional selectivity showed that the CaSR is a promiscuous receptor which activates eight G proteins and that clinically approved CaSR allosteric modulators can promote biased signalling. In summary, my thesis illustrates the importance of Gα<sub>11</sub> for CaSR signalling, demonstrated by identification of additional FHH2 mutants, and that Gα11 mutations disrupt signalling by other GPCRs, thereby possibly leading to wider effects. Additionally, CaSR biased-signalling highlights the importance of G proteins other than Gα11 for this GPCR.</p> |
| spellingShingle | Genetics Metabolism Endocrinology Cell signalling Glück, AK The role of G protein alpha 11 in calcium and glucose homeostasis |
| title | The role of G protein alpha 11 in calcium and glucose homeostasis |
| title_full | The role of G protein alpha 11 in calcium and glucose homeostasis |
| title_fullStr | The role of G protein alpha 11 in calcium and glucose homeostasis |
| title_full_unstemmed | The role of G protein alpha 11 in calcium and glucose homeostasis |
| title_short | The role of G protein alpha 11 in calcium and glucose homeostasis |
| title_sort | role of g protein alpha 11 in calcium and glucose homeostasis |
| topic | Genetics Metabolism Endocrinology Cell signalling |
| work_keys_str_mv | AT gluckak theroleofgproteinalpha11incalciumandglucosehomeostasis AT gluckak roleofgproteinalpha11incalciumandglucosehomeostasis |