The Biochemical Effect of the Naturally Occurring Trp644→Arg Mutation on Human β3‐Adrenoceptor Activity

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<jats:p>A Trp→Arg mutation at amino acid position 64 in the human β3‐adrenoceptor is reportedly associated with morbid obesity; carriers suffer from increased gain in mass, early‐onset diabetes, insulin resistance, and an increased waist‐to‐hip ratio [Clément, K., Vaisse, C., Manning, B. S., Basdevant, A., Guy‐Grand, B., Ruiz, J., Silver, K. D., Shuldiner, A. R., Froguel, R & Strosberg, A. D. (1995) <jats:italic>N. Engl. J. Med. 333</jats:italic>, 352–3541. Here, we report the stable expression of the genes encoding the wild‐type or the [Arg64]β3‐adrenoceptor in two different cell types: hamster CHO‐K1 and human HEK293. The mutated receptor displayed unchanged pharmacological values compared to the wild type for the binding inhibition (<jats:italic>K</jats:italic><jats:sub>i</jats:sub>) and adenylyl cyclase activation constants (<jats:italic>K</jats:italic><jats:sub>act</jats:sub>) in two independent clones of both cell lines. However, maximal cAMP accumulation was significantly reduced in response to various β3‐adrenergic agonists, including endogenous catecholamines, (−)‐epinephrine and (–)‐norepinephrine, the non‐selective agonist (−)‐isoproterenol, and the β3‐adrenergic selective agonist CGP 12177A. Treatment with <jats:italic>Pertussis</jats:italic> toxin did not restore the adenylyl cyclase activity to that of the wild type, suggesting that the reduction in cAMP accumulation observed in cells expressing [Arg64]β3‐adrenoceptor is not due to enhanced interaction of the β3‐adrenoceptor with the inhibitory G<jats:sub>i</jats:sub> protein.</jats:p>

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