title: Effects of dietary-induced hyperparathyroidism on the parathyroid hormone-receptor-adenylate cyclase system of canine kidney. Evidence for postreceptor mechanism of desensitization.
abstract: The present studies were designed to examine the consequences of chronic mild elevations of endogenous parathyroid hormone (PTH) in vivo on the PTH receptor-adenylate cyclase system of canine kidney cortex. Hyperparathyroidism was induced in normal dogs by feeding a diet low in calcium, high in phosphorus to the animals for a period of 6-9 wk. This maneuver resulted in a two to threefold increase in the plasma levels of carboxy-terminal immunoreactive PTH. This degree of hyperparathyroidism is similar to that seen in patients with hyperparathyroidism and normal renal function. After 6-9 wk on the diet the animals were killed and basolateral renal cortical membranes prepared for the study of the PTH receptor-adenylate cyclase system in vitro. The dietary hyperparathyroidism resulted in desensitization of the PTH-responsive adenylate cyclase (Vmax 3,648 +/- 654 pmol cyclic (c)AMP/mg protein per 30 min in hyperparathyroid animals vs. 5,303 +/- 348 in normal controls). The Kact (concentration of PTH required for half-maximal enzyme activation) was unchanged. However, PTH receptor binding (125I-norleucyl8-norleucyl18-tyrosinyl34, 125I[Nle8, Nle18, Tyr34] bPTH (1-34) NH2 as radioligand) was not different in the two groups of animals. Thus, dietary hyperparathyroidism resulted in an uncoupling of the PTH receptor-adenylate cyclase system. This defect was not corrected by guanyl nucleotides in vitro, and the effects of guanyl nucleotides on PTH binding and enzyme activation appeared normal. NaF-stimulated enzyme activity was reduced in the hyperparathyroid animals (8,285 +/- 607 pmol cAMP/mg protein per 30 min vs. 10,851 +/- 247 in controls). These data indicate that desensitization of the PTH-responsive adenylate cyclase system of canine kidney as a result of mild chronic elevations of endogenous PTH is due to a postreceptor defect, demonstrable by NaF activation, not corrected by guanyl nucleotides, leading to abnormal PTH-receptor adenylate cyclase coupling.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000008:administration & dosage; D004032:Diet; D004285:Dogs; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006961:Hyperparathyroidism / Q000209:etiology / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology; D010758:Phosphorus / Q000008:administration & dosage; D011956:Receptors, Cell Surface / Q000032:analysis* / Q000378:metabolism; D018016:Receptors, Parathyroid Hormone; D012969:Sodium Fluoride / Q000494:pharmacology
chemical_list: D011956:Receptors, Cell Surface; D018016:Receptors, Parathyroid Hormone; D010758:Phosphorus; D008345:Manganese; D006160:Guanosine Triphosphate; D012969:Sodium Fluoride; D000262:Adenylyl Cyclases; D002118:Calcium