Researchers from University Hospitals and Case Western Reserve University identified a novel method to isolate the advantageous effects of β2AR stimulation in a mouse model study published in Molecular Cell. It provides a new therapeutic strategy for ailments involving abnormal GPCR function, such as respiratory diseases and many other illnesses.
β2-adrenergic Receptor
The GPCRs linked to Gq are the primary mediators of airway smooth muscle (ASM) contraction and increased airway resistance, according to the National Library of Medicine. However, the Gs-coupled beta-2-adrenoceptor (β2AR) encourages pro-relaxant signaling in and relaxing of ASM, leading to improved airway patency and the reversal of potentially fatal bronchoconstriction.
The β2-adrenergic receptor (β2AR) is the target of several medications used to treat asthma and other obstructive lung conditions. According to PNAS, the receptor (β2AR) is a typical G protein-coupled receptor. It encourages cAMP production by preferentially coupling to the stimulating G protein Gs. Functional investigations have demonstrated that the β2AR also connects to the inhibitory G protein Gi, whose activation prevents cAMP synthesis.
When triggered, the GPCR quickly promotes airway relaxation. However, excessive use of these drugs is linked to poor health outcomes, including mortality, which has reduced their usefulness as first-line treatments.
The β2-adrenergic receptor is crucial for maintaining the permeability of airways, and it is frequently used as a model for the functioning of GPCRs, which account for 50% of all pharmacological targets, according to the researchers.
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Key Molecule in the β2AR Feedback Loop
The finding demonstrates a clear advantage for people with asthma and serves as a model for GPCR modulation. It creates a space for an extensive study aimed at exploiting the therapeutic advantages of GPCRs.
All GPCRs, including the β2AR, function through a feedback loop in which the chemicals that the receptors assist in producing can go full circle and turn off or inactivate the receptors.
Nitric oxide is a crucial component of the β2AR feedback loop, as demonstrated in the recent study. Nitric oxide generation following β2AR stimulation facilitates airway relaxation, but excessive production of the molecule also inactivates β2AR, which causes bronchoconstriction.
"If you prevent that feedback, you're left with a very powerful airway relaxant that before now had not been thought to be that important in airway relaxation," said Jonathan S. Stamler, MD, President, Harrington Discovery Institute at UH.
The research also shows that mice with a particular mutation in the β2AR gene, which inhibits nitric oxide from binding to and inactivating the receptor, are resistant to inflammation, bronchoconstriction, and asthma.
The β1 adrenergic receptor and the angiotensin II receptor 1 are two more GPCR receptors identified in the study as being controlled by nitric oxide-based protein modification.
Stamler said nitric oxide should be regarded as a crucial new player in how this class of receptors works. It's responsible for both the beneficial effects of the receptors and turning them off.
If it could be understood how they're being turned off and how the nitric oxide is popping onto the receptor, it could be blocked. Then you will be left with a new pathway for opening airways.
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