The odd couple: Unlikely receptor pair key to failed asthma treatments

During an asthma attack, a group of drugs known as beta2 agonists can activate the beta2-adrenergic receptor (beta2AR) present on airway smooth muscle cells, causing the airways to relax and the attack to subside. These receptors often exist in identical pairs called homodimers. More recently it has been revealed that some receptor types can exist in a pair with a different receptor, resulting in a heterodimer. In a study appearing in the May issue of the Journal of Clinical Investigation, Stephen Liggett and colleagues from the University of Maryland show that beta2AR can pair with another receptor on airway smooth muscle cells known as EP1R. Activation of this heterodimer causes beta2AR to become uncoupled from its normal signaling pathway, thereby reducing the ability of beta2 agonists to bring about airway relaxation during an asthma attack. This may be why some beta2AR–-activating drugs are not effective in some asthmatics.

Activation of EP1R by the hormone prostaglandin E2 (PGE2) causes airway smooth muscle cell constriction. In their current study, Liggett and colleagues found that PGE2 promotes the pairing or "dimerization" of EP1R with beta2AR, uncoupling b2AR from its signaling cascade, and reducing it's ability to cause muscle relaxation in response to beta2-AR–activating drugs. This may explain why in individuals with severe asthma whose PGE2 levels are elevated, some beta2-AR–-activating drugs are not effective.

In an accompanying commentary, Peter Barnes from Imperial College London reinforces how important the functional consequence of such receptor interactions can be. He muses about "the possibility of finding unexpected drug interactions or novel therapeutic agents that selectively activate certain heterodimer pairs" as well as the possibility of developing more selective drugs in the future for the treatment of asthma in individuals for whom current therapies have proven ineffective.

TITLE: Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex

AUTHOR CONTACT:
Stephen B. Liggett
University of Maryland School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 706-6256; Fax: (410) 706-6262; E-mail: sligg001@umaryland.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=25840

ACCOMPANYING COMMENTARY

TITLE: Receptor heterodimerization: a new level of cross-talk
AUTHOR CONTACT:
Peter J. Barnes
National Heart and Lung Institute, Imperial College, London, United Kingdom.
Phone: 44-207-351-8174; Fax: 44-207-351-5675; E-mail: p.j.barnes@imperial.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28535

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