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Decrease in apparent alpha1-adrenoceptor-G protein coupling during maturation in rat aorta.

H Gurdal1, E Friedman, M D Johnson

  • 1Department of Pharmacology, Medical School of Ankara University, Ankara, Turkey.

The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
|March 5, 2008
PubMed
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Alpha1-adrenoceptor-G protein coupling efficiency decreases with age in rat aortas, leading to reduced norepinephrine potency. This age-related decline in coupling explains lower receptor sensitivity and potency in older animals.

Area of Science:

  • Pharmacology
  • Physiology
  • Molecular Biology

Background:

  • Norepinephrine (NE) elicits a more potent contraction in aortas of young rats compared to older ones.
  • Age-dependent reduction in aortic responsiveness to NE suggests underlying molecular changes.

Purpose of the Study:

  • To investigate the mechanism of age-dependent reduced aortic responsiveness to NE.
  • To examine alpha1-adrenoceptor-guanine nucleotide regulatory binding protein (G protein) coupling efficiency in rat aortic membranes.

Main Methods:

  • Assessed alpha1-adrenoceptor-G protein coupling using guanosine 5'(betagamma-imido)triphosphate (Gpp[NH]p)-induced shift in agonist binding affinity.
  • Measured NE binding affinity by displacement of [125I]-HEAT in aortic membranes from rats of different ages (1, 6, and 24 months).

Related Experiment Videos

Main Results:

  • High-affinity binding of NE to alpha1-adrenoceptors was sensitive to Gpp(NH)p in 1-month-old rats, indicating efficient receptor-G protein interaction.
  • Gpp(NH)p-sensitive high-affinity binding was absent in 6- and 24-month-old rats, despite NE inducing maximal contraction at lower potency.
  • A partial reduction in alpha1-adrenoceptor-G protein coupling between 1 and 6 months correlated with decreased agonist potency and loss of Gpp(NH)p-sensitive binding.

Conclusions:

  • A reduction in alpha1-adrenoceptor-G protein coupling efficiency contributes to the age-dependent decrease in aortic responsiveness to NE.
  • Altered allosteric coupling between ligand binding and G protein interaction, potentially due to changes in alpha1-adrenoceptor subtype expression, underlies this age-related decline.