Altered activity of the nucleotide regulatory site in the parathyroid hormone-sensitive adenylate cyclase from the renal cortex of a patient with pseudohypoparathyroidism.

Abstract

A B S T R A C T A series of clinical studies suggest that the primary defect underlying pseudohypoparathyroidism is an abnormality of the parathyroid hormonereceptor-adenylate cyclase complex of the renal cortical cell plasma membrane. In the present study we compared parathyroid hormone-stimulated adenylate cyclase activity in membrane preparations from the renal cortex of three controls and a patient with pseudohypoparathyroidism. In the pseudohypoparathyroid preparation the Km for ATP was significantly greater and parathyroid hormone elicited markedly diminished adenylate cyclase activity at a subsaturating concentration of ATP. In contrast, the dose-response effect of enzyme activity to parathyroid hormone was the same in the control preparations, and that of the pseudohypoparathyroidism kidney, at a saturating concentration of ATP. The apparent alteration in enzyme kinetics, however, was normalized upon addition of guanosine 5'-triphosphate to the reaction mixtures. These results indicate that the defect in the parathyroid hormone-receptor-adenylate cyclase complex of the renal cell membranes, in our patient with pseudohypoparathyroidism, is an abnormal nucleotide receptor site of decreased activity. Such a defect may result in partial uncoupling of the parathyroid hormone receptor and adenylate cyclase, rendering the organ refractory to hormonal stimulation.

Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.

“…As noted, this hypothesis was confirmed by our observations. These data are consistent with the notion that in PHP-Ia patients a quantitative defect in a single gene product (i.e., N or some component thereof) might be responsible both for the ligand binding abnormalities demonstrated in this work and for decreased adenylate cyclase activation demonstrated in other work (12,17). Our findings further support the idea of a single bifunctional N protein that interacts with both R and C.…”

“…Several lines of evidence have suggested decreased activity of this N protein in activating adenylate cyclase in various tissues (including circulating cells) of some patients with PHP (PHP-Ia) most of whom had Albright's hereditary osteodystrophy (12)(13)(14)(15)(16)(17). By contrast, phenotypically normal patients, who demonstrate abnormal urinary cAMP excretion in response to parathyroid (PTH) infusion, have normal assayable N protein activity in circulating cells (PHP-Ib).…”

Decreased bioactivity of the guanine nucleotide-binding protein that stimulates adenylate cyclase in hearts from cardiomyopathic Syrian hamsters.

“…We detected only the 45,000 mol wt form on immunoblots from hamster cardiac membranes. Considering the amino acid sequence of aG, is highly conserved among mammals (12,13,31,35), our finding that antisera directed against the carboxyl terminus of bovine aG, cross-reacted readily with hamster aG, is not surprising.…”

Cellular Action of Vasopressin in Medullary Tubules of Mice with Hereditary Nephrogenic Diabetes Insipidus

“…2). An abnormally high requirement of adenylate cyclase for GTP (33) seems to be ruled out. These features would suggest a defect in the catalytic subunit of adenylate cyclase, which is not specifically related to AVP effect.…”

“…It was recently reported (33) that adenylate cyclase activity in the renal cortex had a higher dependency on GTP in the kidney of a pseudohypoparathyroid patient than in a normal kidney (33); therefore, we explored whether this factor might account for differences in adenylate cyclase activities in tubules of NDI and control mice. Addition of 10 ,IM GTP had no effect on either basal or AVP-stimulated adenylate cyclase in MCT or MAL of either control or NDI mice (data not shown).…”