Intracellular third loops in AT1 and AT2 receptors determine subtype specificity

The recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven transmembrane G-protein coupled receptor superfamily with a relative ly low sequence homology with the angiotensin IT type 1 (AT1) receptor subt ype and counteracts the growth action of AT1 receptor. Intracellular third loops are known to be involved in interactions with various G proteins. We hypothesized that the intracellular third loop plays critical roles in dete rmining the specificity of opposite functions of AT1 and AT2 receptor subty pes and examined this possibility using chimeric AT1 receptor, of which int racellular third loop is replaced with that of AT2 receptor. We transfected this chimeric receptor into PC12 cells and observed that stimulation of th is receptor inhibited extracellular signal-regulated kinase (ERK) activatio n and induces apoptosis, whereas the binding characteristics of this recept or remained those of AT1 receptor. Taken together, these results support th e notion that intracellular third loop is the critical determinant for mutu ally antagonistic AT1 and AT2 receptors' signaling pathways. (C) 2001 Elsev ier Science Inc. All rights reserved.