Novel role for nitric oxide in treatment of asthma and other obstructive airway diseases detailed by team at University Hospitals and Case Western Reserve University
Image credit: Alan Levine via Wikimedia (CC BY 2.0)
Many therapeutics for asthma and other obstructive lung diseases target the β2-adrenergic receptor (β2AR), a G protein-coupled receptor (GPCR) that rapidly supports airway relaxation when stimulated. Yet, overuse of these agents is associated with adverse health outcomes, including death, which has limited their utility as frontline therapies.
Now, a mouse model study published in the issue of Molecular Cell, from investigators at Case Western Reserve University and University Hospitals (UH), identifies a novel strategy to isolate the beneficial effects of β2AR stimulation. This suggests a new therapeutic approach to airway diseases and numerous other conditions involving the aberrant function of GPCRs.
“Not only is the β2-adrenergic receptor the mainstay for keeping airways open, it’s often studied as a prototype for how GPCRs work, which constitute the targets of 50% of all drugs,” explained Jonathan S. Stamler, professor of Medicine and Biochemistry at Case Western Reserve University School of Medicine, president of the Harrington Discovery Institute at UH, and Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation.
“Our discovery highlights an obvious benefit to asthma and exemplifies what to expect in GPCR regulation. It opens the area for broad-based research in maximizing the therapeutic benefits of GPCRs.”
All GPCRs, including the β2AR, operate via a feedback loop in which the same molecules that the receptors help generate can circle back and turn the receptors “off” or inactivate them. In the new study, the research team reveals nitric oxide to be a key molecule in the β2AR feedback loop, showing that nitric oxide production after β2AR stimulation mediates airway relaxation. Still, overproduction of the molecule also inactivates β2AR, leading to bronchoconstriction.
“If you prevent that feedback, you’re left with a potent airway relaxant that before now had not been thought to be that important in airway relaxation,” said Stamler.
The study also demonstrates that mice harboring a specific mutation in the β2AR gene that prevents nitric oxide from binding to and inactivating the receptor are resistant to bronchoconstriction, inflammation, and asthma.
Other GPCR receptors shown in the study to be regulated by nitric oxide-based protein modification include the β1 adrenergic receptor and the angiotensin II receptor 1.
“Nitric oxide should be thought of as a key new player in how this class of receptors works,” Stamler added. “It’s responsible for both the beneficial effects of the receptors and for turning them off. And if you can understand how they’re being turned off—how that nitric oxide is popping on to the receptor—and you can block that, you will be left with a new pathway for opening airways. The next step in our research will focus on leveraging this new pathway therapeutically.”
Source: Case Western Reserve University