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

ANG II type 1 (AT(1)) 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 hyp othesized that AT(1) receptor downregulation occurs independently of recept or endocytosis or G protein coupling. Mutant AT(1) receptors with carboxy-t erminal deletions internalized <5% of radioligand compared with 65% for wil d-type AT(1) receptors. The truncated AT(1) receptors retained the ability to undergo downregulation. These data suggest the existence of an alternati ve pathway to AT(1) receptor degradation that does not require endocytosis, per se. Point mutations in either the second transmembrane region or secon d intracellular loop impaired G protein (G(q)) coupling. These receptors ex hibited a biphasic pattern of downregulation. The earliest phase of downreg ulation (0-2 h) was independent of coupling to G(q) but no additional downr egulation was observed after 2 h of ANG II exposure in the receptors with i mpaired coupling to G(q). These data suggest that coupling to G(q) is requi red for the later phase (2-24 h) of AT(1) receptor downregulation.