Human chorionic gonadotropin-induced heterologous desensitization of rabbit luteal adenylyl cyclase is associated with altered receptor and G-protein function.
We injected hCG into pseudopregnant rabbits on day 7 of pseudopregnancy and analyzed changes in the components of luteal adenylyl cyclase system in order to determine which components are responsible for altered hormonal responsiveness upon desensitization. hCG-induced desensitization was homologous (loss of responsiveness to LH) early (first 6 h), then became heterologous (partial loss of responsiveness to catecholamines) later (12-48 h). The total number of LH receptors was reduced approximately 30% 3 h after treatment at a time when LH stimulation of adenylyl cyclase activity was not altered. Total LH receptors remained at this level until 24 h, when total receptors were reduced by 88%. While total LH receptor number remained constant, LH-stimulated adenylyl cyclase activity was declining to 57% of the control value at 12 h. Available unoccupied LH receptors were reduced by 96% at 12 h. The affinity of the occupied receptors was reduced 4-fold before down-regulation. The changes in beta-adrenergic receptor number paralleled the changes in catecholamine responsiveness. hCG treatment also altered luteal G-protein function, as assessed by reconstitution of adenylyl cyclase activity in S49 cyc- lymphoma membranes and ADP ribosylation by cholera and pertussis toxins. Isoproterenol (ISO)-reconstituting activities of luteal Gs (the stimulatory G-protein of adenylyl cyclase) were depressed by 65% 12-48 h after hCG treatment, the same time as reduced catecholamine responsiveness. In contrast, NaF-reconstituting activities were at control levels at 12 h and reduced by 55% at 24 and 48 h. Pertussis toxin's ability to ADP ribosylate alpha i 40 was increased 3 and 6 h after treatment, while cholera toxin's ability to ADP ribosylate alpha s 45 was reduced throughout the study period. These studies demonstrate that hCG-induced heterologous desensitization results in a complex series of changes in beta-adrenergic and LH receptors as well as G-protein function, which account for the altered hormonal responsiveness.
Jena
B P
BP
Department of Zoology, Iowa State University of Science and Technology, Ames 50011-3223.
Abramowitz
J
J
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002772:Cholera Toxin; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D003338:Corpus Luteum / Q000032:analysis / Q000502:physiology* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D007986:Luteinizing Hormone / Q000032:analysis / Q000502:physiology; D037342:Pertussis Toxin; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D011974:Receptors, LH / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D010566:Virulence Factors, Bordetella
D037361:Adenylate Cyclase Toxin; D006063:Chorionic Gonadotropin; D011943:Receptors, Adrenergic, beta; D011974:Receptors, LH; D010566:Virulence Factors, Bordetella; D007986:Luteinizing Hormone; D002772:Cholera Toxin; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases