Beta-2 adrenergic receptor dysfunction and polymorphism in asthma
- Ian P Hall, MD
Ian P Hall, MD
- Professor in Molecular Medicine
- University Hospital, Nottingham, UK
- Section Editors
- Peter J Barnes, DM, DSc, FRCP, FRS
Peter J Barnes, DM, DSc, FRCP, FRS
- Editor-in-Chief — Pulmonary and Critical Care Medicine
- Section Editor — Asthma
- Professor of Medicine
- National Heart and Lung Institute, Imperial College, London
- Benjamin A Raby, MD, MPH
Benjamin A Raby, MD, MPH
- Section Editor — Genetics
- Associate Professor of Medicine
- Harvard Medical School
While the powerful bronchodilatory properties of beta adrenergic agonists have been appreciated for many years, understanding of the molecular basis of their activity at the beta-2 adrenergic receptor did not begin until the late 1980s. The mechanisms of signal transduction from this receptor and the potential role of beta-2 adrenergic receptor dysfunction in the pathogenesis of asthma and its response to therapy will be reviewed here. The clinical use of beta agonists in the treatment of asthma is discussed separately. (See "Beta agonists in asthma: Acute administration and prophylactic use" and "Beta agonists in asthma: Controversy regarding chronic use".)
NORMAL RECEPTOR REGULATION
The gene encoding the beta-2 adrenergic receptor is situated on chromosome 5q31 . It encodes a protein that is a member of the large family of G-protein coupled, seven transmembrane-spanning domain receptors. The receptor is expressed on a variety of cell types in the lung, including airway smooth muscle and epithelial cells, vascular endothelium and smooth muscle cells, and inflammatory cells such as mast cells, eosinophils, and lymphocytes.
Stimulation of the beta-2 receptor results in activation of the associated G-protein, Gs, which dissociates to release a protein subunit, free Gs-alpha. Gs-alpha in turn activates adenylyl cyclase, resulting in a rise in intracellular cyclic adenosine monophosphate (AMP) levels. Most of the intracellular effects of beta-2 adrenergic receptor stimulation are due to the elevation in cyclic AMP and consequent activation of protein kinase A (PKA); there may also be direct, cyclic AMP-independent effects of Gs-alpha on the calcium-activated potassium channel [2,3]. (See "Peptide hormone signal transduction and regulation", section on 'G proteins'.)
The expression of beta-2 adrenergic receptors and their coupling with intracellular signaling pathways are dynamically regulated, providing a negative feedback loop that reduces cell responsiveness to long-term occupation of the receptor by an agonist. Phosphorylation of the receptor, either by PKA-dependent pathways or by activation of one of a family of G-protein receptor kinases termed beta-adrenergic receptor kinase (beta-ARKs), leads to reduced coupling with the intracellular signaling pathway following agonist stimulation. Different tissues vary in the degree of uncoupling seen with prolonged agonist exposure, probably due to differences in the amount and activity of beta-ARK and/or PKA in different cell types.
The number of receptors also is actively regulated.
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- NORMAL RECEPTOR REGULATION
- RECEPTOR DYSFUNCTION IN ASTHMA
- RECEPTOR POLYMORPHISMS
- Clinical significance
- - Treatment response to regular SABA
- - Treatment response to LABA
- - Response to ultra-LABAs
- - Acute treatment response to SABA
- - Disease risk
- Cross talk with other signaling cascades