Correspondence

Polymorphisms of the β₂-Adrenergic Receptor

N Engl J Med 2002; 346:536-538February 14, 2002

Article

To the Editor:

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 1Figure 1Static and Dynamic Models of the Regulation of Polymorphic Receptors.) 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.

The results of Dishy et al. are partially consistent with our in vitro studies if one considers the dynamic model: persons with a substitution of glycine for arginine at position 16 (Gly16) do not have desensitization, yet in vitro this receptor has enhanced down-regulation; on the other hand, persons with the wild-type allele, Arg16, have desensitization in vivo, but there is less down-regulation of this receptor in vitro.2 A similar finding has been reported in patients with asthma: patients who are homozygous for Arg16, but not those who are homozygous for Gly16, have tachyphylaxis to regularly scheduled albuterol.5 These issues also highlight the necessity of both clinical and basic studies to delineate the physiological consequences and molecular mechanisms of clinically relevant polymorphisms.

Stephen B. Liggett, M.D.
University of Cincinnati College of Medicine, Cincinnati, OH 45267

5 References

1. 1

   Dishy V, Sofowora GG, Xie H-G, et al. The effect of common polymorphisms of the β₂-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 2001;345:1030-1035
   Full Text | Web of Science | Medline

2. 2

   Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human β₂-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994;33:9414-9419[Erratum, Biochemistry 1994;33:14368.]
   CrossRef | Web of Science | Medline

3. 3

   Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of β₂-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995;13:25-33
   Web of Science | Medline

4. 4

   Liggett SB. Pharmacogenetic applications of the Human Genome Project. Nat Med 2001;7:281-283
   CrossRef | Web of Science | Medline

5. 5

   Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the β₂-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162:75-80
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We are grateful to Dr. Liggett for his comments. In fact, we have previously shown that β₂-adrenergic receptors are indeed dynamically regulated by endogenous catecholamines in vivo,1,2 and therefore we had considered his suggestion — that persons with the Gly16 variant of the β₂-adrenergic receptor, which has enhanced down-regulation in vitro, did not have further tachyphylaxis in vivo because they were already desensitized in response to endogenous catecholamines. Although we could not definitively exclude the possibility that the Gly16 variants were already desensitized, we thought it unlikely because, as shown in Table 2 of our article, the initial responses to isoproterenol in subjects who were homozygous for Arg16 or Gly16 (but matched for glutamine at position 27 [Gln27]) did not differ, whereas as illustrated in the bottom panel of Dr. Liggett's figure, preexisting desensitization in subjects homozygous for Gly16 should result in a decreased initial response to an agonist. Other factors that may account for differences between studies of adrenergic-receptor regulation performed in vitro and in vivo include different concentrations and duration of agonist exposure and modulation of responses by other genetic or homeostatic mechanisms. We agree that our findings illustrate the critical importance of studying the functional effects of genetic variations in vivo as well as in vitro.

Victor Dishy, M.D.
C. Michael Stein, M.D.
Alastair J.J. Wood, M.D.
Vanderbilt University School of Medicine, Nashville, TN 37232-6602

2 References

1. 1

   Fraser J, Nadeau J, Robertson D, Wood AJ. Regulation of human leukocyte beta receptors by endogenous catecholamines: relationship of leukocyte beta receptor density to the cardiac sensitivity to isoproterenol. J Clin Invest 1981;67:1777-1784
   CrossRef | Web of Science | Medline

2. 2

   Feldman RD, Limbird LE, Nadeau J, FitzGerald GA, Robertson D, Wood AJ. Dynamic regulation of leukocyte beta adrenergic receptor-agonist interactions by physiological changes in circulating catecholamines. J Clin Invest 1983;72:164-170
   CrossRef | Web of Science | Medline

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   N. Hizawa. (2009) Beta-2 adrenergic receptor genetic polymorphisms and asthma. Journal of Clinical Pharmacy and Therapeutics 34:6, 631-643
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   Peter J. Barnes, Jeffrey M. Drazen. 2009. Pathophysiology of Asthma. , 399-423.
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   ERIC M. SNYDER, MINELLE L. HULSEBUS, STEPHEN T. TURNER, MICHAEL J. JOYNER, BRUCE D. JOHNSON. (2006) Genotype Related Differences in ??2 Adrenergic Receptor Density and Cardiac Function. Medicine & Science in Sports & Exercise 38:5, 882-886
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    R LANDAU. (2005) Pharmacogenetics: implications for obstetric anesthesia. International Journal of Obstetric Anesthesia 14:4, 316-323
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    Felix W Frueh, David Gurwitz. (2004) From pharmacogenetics to personalized medicine: a vital need for educating health professionals and the community. Pharmacogenomics 5:5, 571-579
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    Kersten M. Small, Dennis W. McGraw, Stephen B. Liggett. (2003) P HARMACOLOGY AND P HYSIOLOGY OF H UMAN A DRENERGIC R ECEPTOR P OLYMORPHISMS. Annual Review of Pharmacology and Toxicology 43:1, 381-411
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    Stephen B. Liggett. (2003) Polymorphisms of Adrenergic Receptors: Variations on a Theme. ASSAY and Drug Development Technologies 1:2, 317-326
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