Constitutively active mutants of the beta1-adrenergic receptor.
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.
Lattion
A
A
Institut de Pharmacologie et Toxicologie, Université de Lausanne, Rue du Bugnon 27, CH-1005, Lausanne, Switzerland.
Abuin
L
L
Nenniger-Tosato
M
M
Cotecchia
S
S
D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000378:metabolism* / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D019943:Amino Acid Substitution; D015784:Betaxolol / Q000378:metabolism / Q000494:pharmacology; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology; D000077261:Carvedilol; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007545:Isoproterenol / Q000378:metabolism / Q000494:pharmacology; D007741:Labetalol / Q000378:metabolism / Q000494:pharmacology; D017354:Point Mutation; D011217:Practolol / Q000378:metabolism / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013999:Timolol / Q000378:metabolism / Q000494:pharmacology
D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D007093:Imidazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011994:Recombinant Proteins; D000077261:Carvedilol; C026777:ICI 118551; D013999:Timolol; C049763:CGP 20712A; D000242:Cyclic AMP; D007545:Isoproterenol; D015784:Betaxolol; D007741:Labetalol; D011217:Practolol; D004837:Epinephrine