The structure and the regulation of the hepatic $ alpha sb1$-adrenergic receptors have been studied in the rat. The in vitro incubation of isolated liver cells in a serum-free buffer for 4 hr leads to the conversion of the adrenergic activation of glycogen phosphorylase from an $ alpha sb1$- to a $ beta$-adrenoceptor-mediated event. This change is associated with no change in the glycogenolytic response to vasopressin and a reduction of the glycogenolytic response to glucagon. The time-dependent shift in the adrenergic control of glycogenolysis does not influence the density or the affinity of ($ sp3$H) prazosin-labeled $ alpha sb1$-receptors and ($ sp3$H) CGP-12177-labeled $ beta$-receptors. The change in the adrenergic control of glycogenolysis is reversed by a 30-min incubation with 50 nM lipomodulin, whereas in freshly isolated cells lipomodulin doesn't affect the predominant $ alpha$-receptor response. Conversely, exposure of freshly isolated cells to a monoclonal antibody to lipomodulin in the presence of 10 $ mu$M phenylephrine, or to 2 $ mu$g/ml mellitin, results in a shift in the adrenergic control of glycogenolysis from $ alpha sb1$- to $ beta$-type within 30 min. It is proposed that coupling of hepatic $ alpha sb1$- and $ beta$-adrenoceptors to postreceptor pathways is regulated in an inverse reciprocal manner by changes in membrane phospholipase A$ sb2$ activity. / The mechanism of activation of the Ca$ sp{2+}$-linked receptors for vasopressin and adrenaline was studied in isolated liver cells. Sequential treatment of cells with 10$ sp{-7}$M vasopressin and 1 mM of bifunctional cross-linker disuccinimidyl suberate (DSS), followed by washout of the drugs, doesn't influence the dissociation of vasopressin from its receptor, but results in permanent activation of glycogen phosphorylase. Similarly, when the cells are stimulated with 10$ sp{-5}$M adrenaline and treated with DSS, glycogen phosphorylase is permanently activated. It is proposed that agonist activation of vasopressin or $ alpha sb1$-adrenergic receptors involves the microaggregation of receptors or their coupling to other membrane proteins. / A novel irreversible antagonist for the $ alpha sb1$-adrenergic receptors, I-phenoxybenzamine (I-POB) has been synthesized and pharmacologically characterized. We have shown that I-POB binds to the $ alpha sb1$-adrenergic receptor in rat liver plasma membranes with high affinity (K$ sb{ rm i}$ = 2 nM). (Abstract shortened with permission of author.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.75667 |
| Date | January 1988 |
| Creators | Tchakarov, Liouben E. |
| 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 Pharmacology and Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 000660399, proquestno: AAINL45920, Theses scanned by UMI/ProQuest. |
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