Pharmacogenomics of beta2-agonist: key focus on signaling pathways.
Asthma is one of the most common respiratory diseases, where inhalation and exhalation are obstructed due to narrowing of the airways by broncho-constriction or by inflammation. Among all the available anti-asthma therapies, beta2-agonists are the most effective bronchodilators available, and give rapid relief of asthma symptoms. Evidence suggests that the degree of beta2-agonist response varies greatly between patients and genetic factors have a major role in it. Despite several studies on the beta2-agonist pharmacogenetics, significant gaps in knowledge still remain and need to be resolved before the pharmacotyping of beta2-agonist responsiveness comes to clinical practice. As we know, beta2-agonists show their influence by targeting beta2-adrenergic receptors, leading to the activation of beta2-adrenergic receptors and its downstream cascade. Signaling through beta2-adrenergic receptors mediates numerous airway functions by regulating broncho-constriction and dilation pathways. Therefore, it is an important prerequisite to understand these pathways, which will assist in defining the variability in therapeutic responses for beta2-agonists. Owing to the complexity of the action of a beta2-agonist and its therapeutic response, a broader genomics approach will help in optimizing therapy for the individual patient. This might be achieved by considering and focusing on receptor/s at which the drug binds directly, signal transduction cascades or downstream proteins and proteins involved in the relaxation and constriction of the airway smooth muscle. Considering that a drug response may involve a large number of proteins, it seems unlikely that a single polymorphism or haplotype in a single gene would explain a high degree of drug response variability in a consistent fashion. Thus, it shows that a polygenic approach will be more appropriate. In order to follow this, the mode of action of the beta2-agonist and its downstream signaling cascade should essentially be assessed to resolve the beta2-agonist enigma.
Bhatnagar
Pallav
P
Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi-110007, India.
Guleria
Randeep
R
Kukreti
Ritushree
R
D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000378:metabolism / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D001483:Base Sequence; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000378:metabolism / Q000494:pharmacology; D006239:Haplotypes; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D018343:Receptors, Adrenergic, beta-2