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Decrease in Apparent Alphax1-Adrenoceptor-G Protein Coupling During Maturation in Rat Aorta
Journal article   Peer reviewed

Decrease in Apparent Alphax1-Adrenoceptor-G Protein Coupling During Maturation in Rat Aorta

Hakan Gurdal, Eitan Friedman, Mark D. Johnson and H. Ongun Onaran
The journals of gerontology. Series A, Biological sciences and medical sciences, v 53A(4), pp B268-B273
Jul 1998
DOI: https://doi.org/10.1093/gerona/53A.4.B268
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

We have previously shown that the adrenoceptor agonist norepinephrine (NE) is more potent in eliciting contractionin aortas from 1-month-old Fischer 344 rats than it is in older animals. In the present study, we examineda\pha,-adrenoceptor-guanine nucleotide regulatory binding protein (G protein) coupling in aortic membranes inorder to investigate the mechanism for the age-dependent reduced responsiveness of aorta to NE. We used theguanosine 5′(βγ-imido)triphosphate (Gpp[NH]p)-induced shift in agonist binding affinity as a measure of the efficiencyof a\pha,-adrenoceptor-G protein coupling. The binding ofNE was assessed by measuring the displacementof 2-[β-(4-hydroxy-3-[125l]iodophenyl)ethylaminomethyl] tetralone ([125]-HEAT) by NE in aortic membranes. In 1-,6-, and 24-month-old rat aortas, two apparent binding sites were detected in the competition isotherms for NE. Thisheterogeneous binding pattern was independent of Gpp(NH)p at all ages, and is likely to be due to a heterogeneousreceptor population (alpha,., alpha,*, and alpha,,, subtypes). In 1-month-old rats, the high affinity binding ofNE toa\p\\a,-adrenoceptors was sensitive to Gpp(NH)p, indicating a significant interaction between the receptor and Gprotein. This Gpp(NH)p-sensitive high affinity binding was not observed in aortas from 6- or 24-month-old animals.Despite the lack of Gpp(NH)p-sensitive high affinity binding of agonist in 6- or 24-month-old aortas, NE was stillable to induce maximal contraction in these aortas, albeit, with a relatively low potency. A partial reduction inalpha,-adrenoceptor-G protein coupling between 1 and 6 months of age can explain the observed decrease in agonistpotency and the loss of Gpp(NH)p-sensitive high affinity binding ofNE. This phenomenon can be explained asa reduction ofallosteric coupling between the bindings ofligandand G protein to the receptor, that has been formulatedin the ternary complex model. Computer simulation using the simple ternary complex model shows thatmanipulating the reciprocal coupling factor alone can lead to a loss of Gpp(NH)p-sensitive high affinity agonistbinding, along with a reduction in agonist potency for contraction without altering the maximal response. Thus, achange in the relative expression of different a\pharadrenoceptor subtypes, which we have previously observed inthe aorta, and which possess diverse intrinsic allosteric couplings, may be speculated to be the mechanism for the apparentreduction of a\pha,-adrenoceptor-G protein coupling during maturation.

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Geriatrics & Gerontology
Gerontology
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