This thesis examines in vivo and in vitro the effects of prolonged exposure of target cells to PTH on PTH receptors and postreceptor components of the adenylate cyclase system. Using a vitamin D-deficient ($-$D) rat model, hyperparathyroidism in vivo resulted in a decreased number of PTH receptors in kidney and a decreased amount of G protein $ alpha$ subunits. The decreased amount of G$ sb{ rm s} alpha$ was shown to be specific for PTH target tissue and may have played a role in the heterologous desensitization of CT-stimulated adenylate cyclase, demonstrated in renal membranes from the $-$D rats. The study of the control of PTH receptors was pursued using an osteosarcoma clonal cell line, UMR-106, in vitro. Initial characterization of these cells revealed abundant, saturable, cell surface PTH receptors linked to the adenylate cyclase system. Demonstration that the majority of PTH binding was associated with morphologically distinct cells in the UMR-106 population indicated that PTH receptors may be maximally expressed during specific stages in the cell cycle. PTH receptors in UMR-106 cells were shown to be regulated by distinct homologous and heterologous mechanisms. PTH-mediated, homologous desensitization was associated with down-regulation of PTH receptors and loss of G$ sb{ rm s} alpha$ protein form the cell membrane. Heterologous desensitization of PTH responses by PGE$ sb2$ was shown to be cAMP mediated, resulting in a reversible modification of the PTH receptors. This work has demonstrated that multiple mechanisms exist for the regulation of PTH responses both in vivo and in vitro that involve modifications of both the PTH receptors and postreceptor components of the adenylate cyclase system.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.74325 |
| Date | January 1989 |
| Creators | Mitchell, Jane |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Physiology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001069296, proquestno: AAINN63644, Theses scanned by UMI/ProQuest. |
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