Signal transduction for adrenergic receptors is regulated by a distinct array of guanine nucleotide binding proteins (G proteins). Our preliminary data indicate that in aorta, (alpha 1b-adrenoceptors (ARs) are linked to both Go and Gq, while (alpha 1d)ARs couple exclusively to Gq. In addition, the levels of various a1 AR subtypes in different blood vessels were different. These results suggest that differential coupling of a1 AR subtypes to G proteins may occur in different blood vessels. These data furthermore suggest that age-related altering the interaction of specific receptor and its associated G protein(s) may significantly affect the receptor-mediated signaling and ultimately the function of the organ. Changes in alpha-and B-AR functions in blood vessels have been reported both in Fisher-344 rats and human. IN addition, an age-related alterations in expression of (alpha)1AR subtypes has also been observed in rat aorta. As aging plays an significant role in mediating the pathogenesis of cardiovascular disease, such as hypertension, orthostatic hypotension and atherosclerosis, it is important to study the molecular mechanism (s) contributing to altered vascular function during aging. The proposed study aims to test the hypothesis that different compositions of alpha (1)AR/G proteins regulate diverse arrays of transmembrane signalling pathways n vasculature which are differentially affected by age. We are proposing a series of experiments to fully characterize the contribution of altered (alpha 1)ARv subtypes/G proteins coupling to the age-related changes in (alpha 1) AR- mediated functions i vasculature. Specifically, we will directly assess linkage of (alpha1) adrenoceptors with G proteins in aortas and tail arteries from young and old rats. Membranes prepared for blood vessels will be used to determine the coupling of (alpha1)-adrenoceptor subtypes to G proteins by an established immunoprecipitation procedure using specific anti-G(alpha) or anti (alpha1 AR antibodies. In addition, we will define the molecular mechanisms responsible for the changes in alpha1 AR transduction systems during aging and test the specificity of these alterations with respect to subclasses of (alpha1 AR, G proteins and blood vessels. Results from the present proposal will greatly enhance our knowledge of the role of the signal transduction pathways in the pathophysiology of age-related cardiovascular diseases and ultimately help in designing specific strategies for more effective pharmacotherapy of those disorders in geriatric patients.
| Gurdal, H; Seasholtz, T M; Wang, H Y et al. (1997) Role of G alpha q or G alpha o proteins in alpha 1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta. Mol Pharmacol 52:1064-70 |
| Seasholtz, T M; Gurdal, H; Wang, H Y et al. (1997) Heterologous desensitization of the rat tail artery contraction and inositol phosphate accumulation after in vitro exposure to phenylephrine is mediated by decreased levels of Galphaq and Galphai. J Pharmacol Exp Ther 283:925-31 |
