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Vol. 55, Issue 6, 1028-1036, June 1999

Relationship between Internalization and mRNA Decay in Down-Regulation of Recombinant Type 1 Angiotensin II Receptor (AT1) Expression in Smooth Muscle Cells

Brian Adams, Tracy S. Obertone, Xiaofei Wang, and T. J. Murphy

Department of Pharmacology (B.A., T.S.O., X.W., T.J.M.) and Graduate Program in Molecular Therapeutics and Toxicology (B.A., X.W., T.J.M.), Graduate Division of Biological and Biomedical Sciences, Emory University School of Medicine, Atlanta, Georgia

In vascular smooth muscle cells, the hormone angiotensin II is thought to cause internalization of the seven-transmembrane domain type 1 angiotensin II receptor (AT1-R) but it also suppresses expression of the receptor mRNA. As for similarly regulated members of this gene superfamily, the relative roles of these processes in receptor down-regulation are not well understood. In this study a recombinant AT1-R mRNA was synthesized in A7r5 vascular smooth muscle cells from a tetracycline-suppressible promoter using a retroviral vector system. Angiotensin II induces a profound internalization of the cell surface AT1-R protein but has no effect on steady-state AT1-R mRNA levels. Shortly after either bolus or prolonged dosing with angiotensin II, cell surface AT1-R expression recovers, indicating the existence of a significant restorative externalization pathway. The extent of this recovery is attenuated markedly when transcription of the recombinant AT1-R gene is suppressed by cotreatment of the cells with anhydrotetracycline. Although agonist-stimulated internalization appears to contribute directly to a loss of AT1-R protein, these observations provide direct evidence that a reduction in AT1-R mRNA content plays a significant role in sustained AT1-R down-regulation.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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