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Vol. 54, Issue 2, 427-434, August 1998
Department of Physiology, Semmelweis University of Medicine, H-1088
Budapest, Hungary (L.H., Z.G., B.M.),
Endocrinology and Reproduction
Research Branch, National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland
20892-4510 (H.J., M.Z., K.J.C.), and
Division of Cardio-Renal
Drug Products, Center for Drug Evaluation and Research, Food and Drug
Administration, Rockville, Maryland 20857 (G.J.)
For several G protein-coupled receptors, amino acids in the seventh
transmembrane helix have been implicated in ligand binding and receptor
activation. The function of this region in the AT1 angiotensin receptor was further investigated by mutation of two conserved polar residues (Asn294 and Asn295) and the adjacent Phe293
residue. Analysis of the properties of the mutant receptors expressed
in COS-7 cells revealed that alanine replacement of Phe293 had no major
effect on AT1 receptor function. Substitution of the
adjacent Asn294 residue with alanine (N294A) reduced receptor binding
affinities for angiotensin II, two nonpeptide agonists (L-162,313 and L-163,491), and the
AT1-selective nonpeptide antagonist losartan but not that
for the peptide antagonist
[Sar1,Ile8]angiotensin II. The N294A receptor
also showed impaired G protein coupling and severely attenuated
inositol phosphate generation. In contrast, alanine replacement of
Asn295 decreased receptor binding affinities for all angiotensin II
ligands but did not impair signal transduction. Additional
substitutions of Asn295 with a variety of amino acids did not identify
specific structural elements for ligand binding. These findings
indicate that Asn295 is required for the integrity of the intramembrane
binding pocket of the AT1a receptor but is not essential
for signal generation. They also demonstrate the importance of
transmembrane helices in the formation of the binding site for
nonpeptide AT1 receptor agonists. We conclude that the
Asn294 residue of the AT1 receptor is an essential
determinant of receptor activation and that the adjacent Asn295 residue
is required for normal ligand binding.
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