guanylyl-imidodiphosphate and Hyperparathyroidism

To examine whether alterations in parathyroid adenylate cyclase might be associated with glandular hyperfunction, we compared enzyme activity in membranes from 7 normal glands with activity from 18 abnormal and 5 noninvolved glands from patients with primary hyperparathyroidism. Compared with the normal glands, the specific enzyme activity after full stimulation with guanyl-5'yl imidodiphosphate was significantly decreased in both hyperplastic and noninvolved glands from the hyperparathyroid subjects. While the enzyme activity of all tissues could be suppressed by calcium, a twofold higher calcium concentration was required for comparable suppression of the enzyme from adenomas as compared with normal or noninvolved glands. Alterations in the adenylate cyclase complex of hyperplastic parathyroid glands may explain, in part, the elevated "set point" for calcium homeostasis in primary hyperparathyroidism.

Topics: Adenoma; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Adult; Aged; Calcimycin; Calcium; Child; Dose-Response Relationship, Drug; Female; Guanylyl Imidodiphosphate; Humans; Hyperparathyroidism; In Vitro Techniques; Male; Middle Aged; Parathyroid Glands; Parathyroid Neoplasms

Current evidence suggests that parathyroid gland adenylate cyclase is involved in the control of parathyroid hormone (PTH) secretion. Thus, the altered control of PTH release in hyperparathyroidism may relate to altered adenylate cyclase activation. Therefore, we examined adenylate cyclase kinetics in membrane preparations from hyperfunctioning human parathyroid glands and normal human and bovine parathyroid tissues. There were no differences in the affinity for ATP between enzymes of normal and pathological tissue. However, the enzyme in 10 hyperfunctioning glands showed increased affinity for Mg++. The activation constant for Mg++ (KaMg) of adenylate cyclase in normal human glands was 10.6 +/- 2 mM, a value not different from that of normal bovine parathyroid tissue (9.5 +/- 1 mM). In contrast, the adenylate cyclase in membrane preparations from three of four hyperplastic and six of seven adenomatous human glands showed a markedly reduced KaMg, ranging from 0.85-1.64 mM and from 1.58-6.46 mM, respectively. In one adenoma and one hyperplastic gland, the Ka of the enzyme for Mg++ was close to normal. The addition of guanylylimidodiphosphate or GTP to the incubation mixture increased, in a dose-dependent manner, the apparent KaMg of the enzyme in the abnormal tissue toward normal, suggesting a defective nucleotide regulatory site in the adenylate cyclase of hyperparathyroid glands. In addition, the hyperparathyroid gland enzyme was less susceptible to inhibition by calcium, requiring 0.7-1 mM Ca++ for 50% inhibition, whereas comparable inhibition of the normal adenylate cyclase was seen at 0.22-0.28 mM Ca++. We conclude that the abnormal control of PTH secretion in hyperparathyroidism may be related, at least in part, to alterations in the characteristics of parathyroid gland adenylate cyclase.

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Animals; Calcium; Cattle; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Humans; Hyperparathyroidism; Kinetics; Magnesium; Parathyroid Glands

Topics: Adenylyl Cyclases; Animals; Biological Assay; Cell Membrane; Dogs; Enzyme Activation; Guanylyl Imidodiphosphate; Humans; Hyperparathyroidism; In Vitro Techniques; Kidney Cortex; Parathyroid Glands; Parathyroid Hormone; Radioimmunoassay; Veins