Abstract
We provide the first evidence that point mutations can constitutively activate the beta(1)-adrenergic receptor (AR). Leucine 322 of the beta(1)-AR in the C-terminal portion of its third intracellular loop was replaced with seven amino acids (I, T, E, F, C, A and K) differing in their physico-chemical properties. The beta(1)-AR mutants expressed in HEK-293 cells displayed various levels of constitutive activity which could be partially inhibited by some beta-blockers. The results of this study might have interesting implications for future studies aiming at elucidating the activation process of the beta(1)-AR as well as the mechanism of action of beta-blockers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic beta-1 Receptor Agonists
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-Agonists / metabolism*
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Adrenergic beta-Agonists / pharmacology
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Adrenergic beta-Antagonists / metabolism*
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Adrenergic beta-Antagonists / pharmacology
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Amino Acid Substitution
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Betaxolol / metabolism
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Betaxolol / pharmacology
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Carbazoles / metabolism
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Carbazoles / pharmacology
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Carvedilol
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Cell Line / drug effects
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Cell Line / metabolism
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Cyclic AMP / metabolism
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Epinephrine / metabolism
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Epinephrine / pharmacology
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Humans
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Imidazoles / metabolism
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Imidazoles / pharmacology
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Isoproterenol / metabolism
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Isoproterenol / pharmacology
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Labetalol / metabolism
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Labetalol / pharmacology
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Point Mutation*
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Practolol / metabolism
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Practolol / pharmacology
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Propanolamines / metabolism
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Propanolamines / pharmacology
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Receptors, Adrenergic, beta-1 / genetics*
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Receptors, Adrenergic, beta-1 / metabolism*
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Receptors, Adrenergic, beta-2 / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Timolol / metabolism
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Timolol / pharmacology
Substances
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Adrenergic beta-1 Receptor Agonists
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-Agonists
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Adrenergic beta-Antagonists
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Carbazoles
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Imidazoles
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Propanolamines
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Receptors, Adrenergic, beta-1
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Receptors, Adrenergic, beta-2
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Recombinant Proteins
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Carvedilol
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ICI 118551
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Timolol
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CGP 20712A
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Cyclic AMP
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Isoproterenol
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Betaxolol
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Labetalol
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Practolol
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Epinephrine