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J. Biol. Chem., Vol. 268, Issue 31, 23116-23121, 11, 1993
SA Green, G Cole, M Jacinto, M Innis and SB Liggett
We have recently identified several naturally occurring variants of the
human beta 2-adrenergic receptor (beta 2AR). One of these polymorphisms,
which is relatively uncommon, is a mutation occurring in the fourth
transmembrane spanning domain, with Ile substituted for Thr at amino acid
164 within the proposed ligand binding pocket. This mutation is adjacent to
Ser165 which has been predicted to interact with the beta-carbon hydroxyl
group of adrenergic ligands. To determine the functional significance of
this variant, we constructed by site- directed techniques a mutated beta
2AR (Ile164) with this substitution and expressed it in CHW-1102 cells. In
the presence of guanine nucleotide, Ile164 displayed a lower binding
affinity for epinephrine as compared with the wild-type beta 2AR (Ki = 1450
+/- 79 versus 368 +/- 39 nM; p < 0.001). A similarly decreased affinity
was found with the catecholamines isoproterenol and norepinephrine, but not
with dobutamine or dopamine which lack hydroxyl groups on their beta-
carbons. In addition, antagonists without aromatic ring polar substituents
displayed a decreased affinity for the mutated receptor. In agonist
competition experiments conducted in the absence of guanine nucleotide,
Ile164 failed to exhibit detectable high affinity binding, suggesting an
impairment in the formation of the agonist-receptor-Gs complex. Consistent
with this finding, functional coupling to Gs as determined in adenylyl
cyclase assays was significantly (approximately 50%) depressed with Ile164
under both basal and agonist-stimulated conditions. beta 2AR sequestration,
which is also triggered by agonist binding, was also found to be
approximately 65% reduced in the Ile164 polymorphism. This study represents
the first characterization of a naturally occurring mutation of a human
adrenergic receptor. Our findings generally support the hypothesized role
of this region of the receptor for ligand binding and receptor activation,
as well as for establishing critical interactions for overall receptor
conformation.
A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor
Department of Medicine (Pulmonary), University of Cincinnati College of Medicine, Ohio 45267-0564.
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L. E. Wagoner, L. L. Craft, B. Singh, D. P. Suresh, P. W. Zengel, N. McGuire, W. T. Abraham, T. C. Chenier, G. W. Dorn II, and S. B. Liggett Polymorphisms of the {beta}2-Adrenergic Receptor Determine Exercise Capacity in Patients With Heart Failure Circ. Res., April 28, 2000; 86(8): 834 - 840. [Abstract] [Full Text] [PDF]
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