Genetic variability of the β₂ adrenergic receptor and asthma exacerbations

The treatment of asthma remains a formidable task for clinicians, despite the development of new treatment options such as long acting β agonists, potent inhaled corticosteroids, and leukotriene receptor antagonists. The complexities in treatment arise not only from temporal changes in the clinical status of patients (such as viral infections and allergy exposures), but also from the well recognised variability between individuals in the response to treatment. This variability is found with the most widely used treatment for asthma—the β agonists—which act to dilate constricted airways by binding to the β₂ adrenoceptor on airway smooth muscle. It has been suggested that up to 50% of the variability in response to β agonists between individuals has a genetic basis.¹ Beta agonists evoke smooth muscle relaxation in airways that have become constricted from virtually any spasmogen, so it is no wonder they have a central role in treating asthma.

However, several aspects of β₂ adrenoceptor signalling have been lurking in the shadows for many years. Firstly, in virtually every cell type that has been studied, chronic exposure (~8 hours or more) to β agonists results in a loss of receptor expression with accompanying desensitisation of the cellular response.² At the physiological level, desensitisation could be manifested as tachyphylaxis. Clinically, tachyphylaxis to β agonists could lead to a variety of outcomes such as progressive loss of the bronchodilating effect, a loss of the protective effect against bronchoconstriction, and increased exacerbations. It has also been recognised for over 25 years that corticosteroids increase β₂ adrenoceptor expression,³ which could mitigate against agonist promoted downregulation.⁴ The clinical response to corticosteroids in asthma may therefore involve both anti-inflammatory effects which reduce local spasmogens, as well as improvement in β₂ adrenoceptor signalling. …