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The Type 1 Angiotensin II Receptor Tail Affects Receptor Targeting, Internalization, and Membrane Fusion Properties

Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin (B.N.B.); Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Veterans Affairs (VA) Medical Center, Nashville, Tennessee (H.C., R.C.H.); and Tulane University Medical Center, Tulane/VA Environmental Astrobiology Center, and New Orleans VA Medical Center New Orleans, Louisiana (T.G.H.)

Endocytosis modulates cell responses by removing and recycling receptors from the cell surface. Type I angiotensin II receptors (AT₁R) are somewhat unique in that they are expressed at apical (AP) and basolateral (BL) membranes in proximal tubule cells and both receptor sites undergo endocytosis. We analyzed AT₁R cytoplasmic (–COOH) tail deletion mutants to determine whether classic AT₁R endocytosis motifs functioned similarly in polarized cells and simultaneously altered receptor properties. Serially truncating the AT₁R tail had little effect on AP/BL AT₁R distribution as determined by ¹²⁵I-angiotensin II binding in LLCPK_Cl4 cells transfected with an AT₁R transcript. AP AT₁R expression required the proximal 12 amino acids in the AT₁R-COOH tail. Deleting all but the proximal 12 aa of the AT₁R-COOH tail (T316L mutant) decreased AP AT₁R internalization at 20 min (17 ± 6%; p < 0.05 versus full-length; n = 5) and inhibited AP AT₁R-stimulated arachidonic acid release (counts released per milligram of protein at 20 min: full-length, 18,762 ± 4018; T316L, 2430 ± 1711; n = 4; p < 0.02). Endosomal fusion assays were performed using peptide sequences of regions in the AT₁R tail involved in endocytosis (YFLQLLKYIPP [LL] and LSTKMSTLSY [STL]). Peptide STL significantly inhibited endosomal fusion (22 ± 10% of control; n = 5; p < 0.05 versus positive control). Peptide LL had no significant inhibitory effect. AT₁R in polarized cells contain dominant endocytosis signals but these motifs do not correlate with AP or BL AT₁R expression. Moreover, peptide sequences within the AT₁R–COOH tail necessary for endocytosis also modulate endosomal fusion properties.

Address correspondence to: Dr. Raymond C. Harris, C-3121 MCN, Vanderbilt University Medical Center, 21st and Garland Ave, Nashville, TN 37232-2372. E-mail: ray.harris{at}vanderbilt.edu.

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