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T Suzuki, CT Nguyen, F Nantel, H Bonin, M Valiquette, T Frielle and M Bouvier
Department of Biochemistry, Universite de Montreal, Canada.
The agonist-induced reduction of beta-adrenergic receptor (beta AR) cell surface density is a well documented phenomenon. The mechanisms responsible for this regulation have been well characterized for the beta 2AR. They include a rapid sequestration of the receptor away from the cell surface in a vesicular compartment and a longer term down- regulation of the total beta 2AR number. In contrast, very little is known about the cell surface regulation of the beta 1AR. In the present study, we have compared the agonist-mediated regulation of beta 1- and beta 2AR in Chinese hamster fibroblasts transfected with the cDNA encoding either beta AR subtype. Cells expressing similar numbers of the two beta AR subtypes were selected for the study. The expressed receptors exhibit typical beta 1- and beta 2AR selectivity for agonists and antagonists, as assessed by radioligand binding. Both receptors were found to be positively coupled to the adenylyl cyclase stimulatory pathway, but marked differences in the receptor regulation profiles were observed. Treatment of the cells expressing the beta 2AR with the agonist isoproterenol leads to a rapid sequestration of greater than 30% of the receptors away from the cell surface into a light vesicular fraction, where they are inaccessible to the hydrophilic ligand CGP- 12177. In contrast, virtually no agonist-induced sequestration is observed in the cells expressing the beta 1AR. Longer exposure of the cells to isoproterenol leads to a time-dependent reduction in the total number of beta ARs in both beta 1- and beta 2AR-expressing cell lines. However, this down-regulation is significantly slower in the cells expressing the beta 1AR. In fact, no appreciable down-regulation of the beta 1ARs is detected in the first 4 hr of agonist treatment, compared with a down-regulation of greater than 50% of the beta 2ARs for the same period. After a 24-hr treatment with isoproterenol, less than 20% of the original number of beta 2ARs remain, whereas 60% of the beta 1ARs are still present after the same treatment. These results, therefore, suggest that, when expressed in an identical cell line, beta 1AR and beta 2AR follow distinct patterns of regulation. In fact, both agonist-induced sequestration and down-regulation are considerably blunted for the beta 1AR, compared with the beta 2AR.
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