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

Heinsimer, James A.; Davies, Albert O.; Downs, Robert W.; Levine, Michael A.; Am, Spiegel; Drezner, Marc K.; Léan, André De; Wreggett, Keith A.; Caron, Marc G.; Lefkowitz, Robert J.

doi:10.1172/jci111336

Cited by 18 publications

(2 citation statements)

References 32 publications

(24 reference statements)

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“…Biochemical assays that measure hormone signaling after reconstitution of patient cell membranes with membranes that totally lack G s (cycϪ) demonstrated that in PHPIA functional G s activity is decreased by approximately 50% in membranes from various cell types, including erythrocytes, fibroblasts, platelets, lymphocytes, and kidney (288,(325)(326)(327)(328)(329)(330)(331)(332)(333)(334)(335). Functional studies in membranes (304,338) and whole cells (339) confirmed that these patients have a defect in G s signaling. Functional studies in membranes (304,338) and whole cells (339) confirmed that these patients have a defect in G s signaling.…”

Section: The Role Of Inactivating G S ␣ Mutations and G S ␣ Imprinmentioning

confidence: 94%

Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting

et al. 2001

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The heterotrimeric G protein G(s) couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate G(s) by promoting exchange of GTP for GDP on the G(s) alpha-subunit (G(s)alpha) while an intrinsic GTPase activity of G(s)alpha that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific G(s)alpha residues (Arg(201) or Gln(227)) that are critical for the GTPase reaction lead to constitutive activation of G(s)-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroidism type IA). Studies in G(s)alpha knockout mice demonstrate that G(s)alpha is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of G(s)alpha expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on G(s)alpha expression or PTH action. G(s)alpha has recently been shown to be also imprinted in human pituitary glands. The G(s)alpha gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products including G(s)alpha, XLalphas (a novel G(s)alpha isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the G(s)alpha promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of G(s)alpha. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease G(s)alpha expression in renal proximal tubules. Studies in G(s)alpha knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metab...

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Section: The Role Of Inactivating G S ␣ Mutations and G S ␣ Imprinmentioning

confidence: 94%

Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting

et al. 2001

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“…This may result from insufficient duration of fetal cortisol exposure or failure to reach a threshold level necessary to induce changes in the myocardium. Alternatively, gestation‐dependent effects may be cortisol‐independent or may require concomitant activity in additional endocrine systems, such as the thyroid axis (Heinsimer et al 1984; Pracyk & Slotkin, 1991, 1992; Birk et al 1992). It is of interest that, although in the current study fetal cortisol infusion failed to have a significant effect on chronotropic and inotropic responses to carbachol or isoprenaline, it did increase basal LV, but not RV, developed pressure.…”

Section: Discussionmentioning

confidence: 99%

Effects of gestational age and cortisol treatment on ovine fetal heart function in a novel biventricular Langendorff preparation

Fletcher¹,

Forhead²,

Fowden³

et al. 2005

The Journal of Physiology

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Structural and functional maturation of a number of fetal organs and physiological systems occurs in the immediate period prior to term, in association with the prepartum increase in fetal plasma cortisol concentration. At present, little is known about how myocardial sensitivity to adrenergic and muscarinic cholinergic stimulation changes as the fetus approaches term, nor the role of the prepartum increase in plasma cortisol concentration in mediating these changes. This study used a novel Langendorff, biventricular, ovine fetal heart preparation to investigate the effects of advancing gestation and cortisol treatment on myocardial sensitivity to adrenergic (isoprenaline) and muscarinic cholinergic ( The Langendorff, isolated, perfused heart preparation is used widely to assess myocardial chronotropic and inotropic responsiveness to exogenous agonists in vitro (Doring, 1990). To date, the preparation has principally been employed in adult rat and rabbit hearts, with measures of heart rate and ventricular contractility being derived from the pressure pulsatility within a fluid-filled latex balloon inserted into the left ventricle (Doring, 1990).

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Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

Moss

Vaughan

1988

Advances in Enzymology - And Related Areas of Molecular Biology

140

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

Cited by 18 publications

References 32 publications

Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting

Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting

Effects of gestational age and cortisol treatment on ovine fetal heart function in a novel biventricular Langendorff preparation

Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

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