Polymorphisms of the β2-Adrenergic Receptor

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Abstract
Dishy et al. (Oct. 4 issue)1 report that polymorphisms of the β2-adrenergic receptor influence agonist-promoted desensitization of β2-adrenergic receptor–mediated vasodilatation. Desensitization can be an important homeostatic event but may also limit the therapeutic effectiveness of agonists (a response called tachyphylaxis). The authors indicate that their findings were unexpected, given results of in vitro studies in which my colleagues and I used polymorphic β2-adrenergic receptors that were expressed in cells in either recombinant2 or native3 form. However, the effect of polymorphisms in vivo is dependent on whether receptors are under static or dynamic regulation. The concept ( Figure 1 ) is broadly applicable and is important to consider, since the number of polymorphic genes studied in cell-based systems and humans will undoubtedly increase during the next few years.4 With static regulation, the typically low levels of endogenous agonists (catecholamines) do not appreciably desensitize receptors under normal circumstances in vivo. Thus, the altered regulatory activities, such as desensitization, that result from a polymorphism are observed only after treatment with an exogenous agonist. In contrast, with dynamic regulation, receptors are also constantly regulated by their endogenous agonists, so that highly sensitive polymorphic receptors are “pre-desensitized” before the challenge of an exogenous agonist is presented. Such receptors might not become further desensitized with the persistent presence of an exogenous agonist, thereby revealing an apparently paradoxical phenotype.