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Altered Adenylate Cyclase Kinetics in Hyperfunctioning Human Parathyroid Glands^*

EZEQUIEL BELLORIN-FONT, KEVIN J. MARTIN, JEFFREY J. FREITAG, CHARLES ANDERSON, GREGORIO SICARD SICARD, EDUARDO SLATOPOLSKY and SAULO KLAHR

Renal Division, Departments of Medicine and Surgery St. Louis, Missouri 63110
Washington University School of Medicine St. Louis, Missouri 63110

Address requests for reprints to: Dr. Ezequiel Bellorin-Font, Renal Division, Box 8126, Department of Internal Medicine, 4550 Scott Avenue, St. Louis, Missouri 63110.

Current evidence suggests that parathyroid gland denylate 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⁺⁺ (Ka_Mg) 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 Ka_Mg, 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 Ka_Mg 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.

^* This work was supported by USPHS NIAMDD Grants AM-09976 and AM-07126.

Recipient of a fellowship from Consejo Nacional de Investigaciones Cientificas y Tecnologicas, Venezuela.

Recipient of a fellowship of the National Kidney Foundation.

Received April 28, 1980.

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