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Papers In Press, published online ahead of print February 24, 2006
J. Biol. Chem, 10.1074/jbc.M508500200
Submitted on August 3, 2005
Revised on February 21, 2006
Accepted on February 23, 2006

Characterization of the residues in helix 8 of the human beta 1-adrenergic aeceptor that are Involved in coupling the receptor to G proteins

Noel M. Delos Santos, Lidia A. Gardner, Stephen W. White, and Suleiman W. Bahouth

Pharmacology Dept., University of Tennessee-Memphis, Memphis, TN 38163

Corresponding Author: sbahouth{at}utmem.edu

Several key amino acids within amphipathic helix 8 of the human ß1-adrenergic receptor (ß1-AR) were mutagenized in order to characterize their role in signaling by G protein-coupled receptors (GPCR). Mutagenesis of phenylalanine at position 383 in the hydrophobic interface to histidine (F383H) prevented the biosynthesis of the receptor, indicating that the orientation of helix 8 is important for receptor biosynthesis. Mutagenesis of aspartic acid at position 382 in the hydrophilic interface to leucine (D382L) reduced the binding and uncoupled the receptor from G protein activation. Mutagenesis of the basic arginine residue at position 384 to glutamine (R384Q) or to glutamic acid (R384E) increased basal and agonist-stimulated adenylyl cyclase activities. R384Q and R384E displayed features associated with constitutively active receptors because inverse agonists markedly reduced their elevated basal adenylyl cyclase activities. Isoproterenol increased the phosphorylation and promoted the desensitization of the Gly389 or Arg389 allelic variants of the wild-type ß1-AR (WT ß1-AR), but failed to produce these effects in R384Q and R384E because these receptors were maximally phosphorylated and desensitized under basal conditions. In contrast to the membranous distribution of the WT ß1-AR, R384Q and R384E were localized mostly within intracellular punctate structures. Inverse agonists restored the membranous distribution of R384Q and R384E, indicating that they recycled normally when their constitutive internalization was blocked by inverse agonists. These data combined with computer modeling of the putative three-dimensional organization of helix 8 indicate that the amphipathic character of helix 8 and side chain projections of Asp382 and Arg384 within the hydrophilic interface might serve as a tethering site for the G protein.


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