oa Functional Crosstalk Between β2-adrenoreceptor and Muscarinic Acetylcholine Receptor: Implications for Gene-Gene Interactions and Bronchodilatory Responses in Patients with Asthma and COPD

Genetic variability in molecular drug targets is increasingly recognized in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD). The long-acting β2 adrenoreceptor (β2AR) agonists and long-acting muscarinic acetylcholine receptor (mAChR) antagonists have been widely used as bronchodilatory therapies in these clinical indications. These treatments are, however, far from ideal and display limited efficacy, particularly in COPD. Specific guidelines on how best to customize therapeutic regimens for individual patients are yet to be formulated. The polymorphisms within the coding block of the β2AR gene are strongly associated with receptor function and affect the long-term response to β2AR agonists in patients with asthma. Two pertinent drug target receptor subtype families, mAChRs and β2ARs, belong to the common seven-transmembrane spanning family of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). Cell biology studies indicate that biosignals from one GPCR can modify another receptor function through intracellular signaling and molecular cross-talk. Thus, it is conceivable that gene-gene (epistatic) interactions between these two receptors may occur, modifying the bronchodilatory response to drugs acting at these molecular targets. In accordance with this, our recent empirical observations suggest that the β2AR genotypes may influence differential bronchodilatory response to anticholinergic agents in patients with COPD and asthma. This review aims to highlight (1) the pharmacogenetic associations of β2AR gene variants with drug response in patients with asthma and COPD and (2) the importance of considering gene-gene interactions for personalization of drug therapy and the value of ‘pathway pharmacogenetics’ more generally.