Akademik Veri Yönetim Sistemi
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, cilt.53, sa.4, 1998 (SCI-Expanded)
We heave previously shown that the adrenoceptor agonist norepinephrine (IVE) is more potent in eliciting contraction ill aortas from 1-month-old Fischer 344 rats than it is in older animals. in the present study, we examined alpha(1)-adrenoceptor-guanine nucleotide regulatory binding protein (G protein) coupling 81 aortic membranes in order to investigate the mechanism for the age-dependent reduced responsiveness of aorta to NE. We used the guanosine S'(beta gamma-imido)tritphosphate (Gpp[NH]p)-induced shift in agonist binding affinity as a measure of the efficiency of alpha(1)-adrenoceptor-G protein coupling. The binding of NE was assessed by measuring the displacement of 2-[beta-(4-hydroxy-3-[(125)l]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 ill the competition isotherms for NE. This heterogeneous binding pattern was independent of Gpp(NH)p at all ages, and is likely to be due to a heterogeneous receptor population (alpha(1a), alpha(1b), and alpha(1d), subtypes). In 1-month-old mts, the high affinity binding of NE to alpha(1)-adrenoceptors was sensitive to Gpp(NH)p, indicating a significant interaction between the receptor and G protein. This Gpp(NH)p-sensitive high affinity binding was not observed ill aortas from 6- or 24-month-old animals. Despite the lack of Gpp(NR)p-sensitive high affinity binding of agonist ill 6- or 24-month-old aortas, NE was still able to induce maximal contraction ill these aortas, albeit, with a relatively low potency. A partial reduction in alpha(1)-anrenoceptor-G protein coupling between I and 6 profiles of age call explain the observed decrease ill agonist potency and the loss of Gpp(NH)p-sensitive high affinity binding of NE. This phenomenon can be explained as a reduction of allosteric coupling between the bindings of ligand and G protein to the receptor, that has been formulated in the ternary complex model. Computer simulation using the simple ternary complex model shows that manipulating the reciprocal coupling factor alone cart lead to a loss of Gpp(NH)p-sensitive high affinity agonist binding, along with a reduction ill agonist potency for contraction without altering the maximal response. This, a change ira the relative expression of different alpha(1)-adrenoceptor subtypes, which,ve have previously observed ill the aorta, and which possess diverse intrinsic allosteric couplings, may be speculated to be the mechanism for the apparent reduction of alpha(1)-adrenoceptor -G protein coupling during maturation.