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

Publication ,  Journal Article
Heinsimer, JA; Davies, AO; Downs, RW; Levine, MA; Spiegel, AM; Drezner, MK; De Lean, A; Wreggett, KA; Caron, MG; Lefkowitz, RJ
Published in: J Clin Invest
May 1984

Decreased activity of the guanine nucleotide regulatory protein (N) of the adenylate cyclase system is present in cell membranes of some patients with pseudohypoparathyrodism (PHP-Ia) whereas others have normal activity of N (PHP-Ib). Low N activity in PHP-Ia results in a decrease in hormone (H)-stimulatable adenylate cyclase in various tissues, which might be due to decreased ability to form an agonist-specific high affinity complex composed of H, receptor (R), and N. To test this hypothesis, we compared beta-adrenergic agonist-specific binding properties in erythrocyte membranes from five patients with PHP-Ia (N = 45% of control), five patients with PHP-Ib (N = 97%), and five control subjects. Competition curves that were generated by increasing concentrations of the beta-agonist isoproterenol competing with [125I]pindolol were shallow (slope factors less than 1) and were computer fit to a two-state model with corresponding high and low affinity for the agonist. The agonist competition curves from the PHP-Ia patients were shifted significantly (P less than 0.02) to the right as a result of a significant (P less than 0.01) decrease in the percent of beta-adrenergic receptors in the high affinity state from 64 +/- 22% in PHP-Ib and 56 +/- 5% in controls to 10 +/- 8% in PHP-Ia. The agonist competition curves were computer fit to a "ternary complex" model for the two-step reaction: H + R + N in equilibrium HR + N in equilibrium HRN. The modeling was consistent with a 60% decrease in the functional concentration of N, and was in good agreement with the biochemically determined decrease in erythrocyte N protein activity. These in vitro findings in erythrocytes taken together with the recent observations that in vivo isoproterenol-stimulated adenylate cyclase activity is decreased in patients with PHP (Carlson, H. E., and A. S. Brickman, 1983, J. Clin. Endocrinol. Metab. 56:1323-1326) are consistent with the notion that N is a bifunctional protein interacting with both R and the adenylate cyclase. It may be that in patients with PHP-Ia a single molecular and genetic defect accounts for both decreased HRN formation and decreased adenylate cyclase activity, whereas in PHP-Ib the biochemical lesion(s) appear not to affect HRN complex formation.

Duke Scholars

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

May 1984

Volume

73

Issue

5

Start / End Page

1335 / 1343

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta
  • Pseudohypoparathyroidism
  • Pindolol
  • Middle Aged
  • Male
  • Iodine
  • Immunology
  • Humans
  • Female
  • Erythrocyte Membrane
 

Citation

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Heinsimer, J. A., Davies, A. O., Downs, R. W., Levine, M. A., Spiegel, A. M., Drezner, M. K., … Lefkowitz, R. J. (1984). Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism. J Clin Invest, 73(5), 1335–1343. https://doi.org/10.1172/JCI111336
Heinsimer, J. A., A. O. Davies, R. W. Downs, M. A. Levine, A. M. Spiegel, M. K. Drezner, A. De Lean, K. A. Wreggett, M. G. Caron, and R. J. Lefkowitz. “Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.J Clin Invest 73, no. 5 (May 1984): 1335–43. https://doi.org/10.1172/JCI111336.
Heinsimer JA, Davies AO, Downs RW, Levine MA, Spiegel AM, Drezner MK, et al. Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism. J Clin Invest. 1984 May;73(5):1335–43.
Heinsimer, J. A., et al. “Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.J Clin Invest, vol. 73, no. 5, May 1984, pp. 1335–43. Pubmed, doi:10.1172/JCI111336.
Heinsimer JA, Davies AO, Downs RW, Levine MA, Spiegel AM, Drezner MK, De Lean A, Wreggett KA, Caron MG, Lefkowitz RJ. Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism. J Clin Invest. 1984 May;73(5):1335–1343.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

May 1984

Volume

73

Issue

5

Start / End Page

1335 / 1343

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta
  • Pseudohypoparathyroidism
  • Pindolol
  • Middle Aged
  • Male
  • Iodine
  • Immunology
  • Humans
  • Female
  • Erythrocyte Membrane