Am J Physiol Cell Physiol Journal of Applied Physiology
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Am J Physiol Cell Physiol 281: C801-C809, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 3, C801-C809, September 2001

ANG II type 1 receptor downregulation does not require receptor endocytosis or G protein coupling

J. Gregory Modrall1, Masakatsu Nanamori2, Junichi Sadoshima3, Douglas C. Barnhart4, James C. Stanley4, and Richard R. Neubig2,3

1 Department of Surgery, Dallas Veterans Affairs Medical Center and the University of Texas Southwestern Medical Center, Dallas, Texas 75235; and Departments of 4 Surgery, 2 Pharmacology, and 3 Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109

ANG II type 1 (AT1) receptors respond to sustained exposure to ANG II by undergoing downregulation of absolute receptor numbers. It has been assumed previously that downregulation involves endocytosis. The present study hypothesized that AT1 receptor downregulation occurs independently of receptor endocytosis or G protein coupling. Mutant AT1 receptors with carboxy-terminal deletions internalized <5% of radioligand compared with 65% for wild-type AT1 receptors. The truncated AT1 receptors retained the ability to undergo downregulation. These data suggest the existence of an alternative pathway to AT1 receptor degradation that does not require endocytosis, per se. Point mutations in either the second transmembrane region or second intracellular loop impaired G protein (Gq) coupling. These receptors exhibited a biphasic pattern of downregulation. The earliest phase of downregulation (0-2 h) was independent of coupling to Gq, but no additional downregulation was observed after 2 h of ANG II exposure in the receptors with impaired coupling to Gq. These data suggest that coupling to Gq is required for the later phase (2-24 h) of AT1 receptor downregulation.

internalization; clathrin-coated pit; radioligand binding assay


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