The Structural Role of the Beta‐2 Adrenergic Receptor Function for the Pharmacological Treatment of Cardiopulmonary Diseases

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Link, Tina, Kona, Abhinav, Dunaway, Katherine, Singh, Siddhant, Stark, Kaylan, Thomas‐Wilkinson, Phillipa
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R4791

As a part of the group of Beta‐Adrenergic receptors (B1, B2, B3), the Beta‐2 Adrenergic receptor is a transmembrane glycoprotein that is principally responsible for the mediation of physiological function over the pulmonary and cardiovascular systems through the binding to the catecholamine, adrenaline (epinephrine). Residing in a larger superfamily of hormone‐activated G‐Protein‐Coupled‐Receptors (GPCR), the B2AR adrenoceptor is composed of 3 extracellular and 5 intracellular alpha helices that are coupled with the heterotrimeric G protein, Gs. When the alpha subunit of Gs is bound to GDP, the B2AR adrenoceptor undergoes structural changes upon activation to transmit the communicative signals to the adenylyl cyclase via the stimulatory G‐protein. Consequently, the B2AR receptor resides in two structural conformations: the active and inactive state, dependent on the binding of the GDP to Gs. The shift in equilibrium between each state in proportion to the strength of the binding agonist has brought about new therapeutic research proposing the in silico screening of new B2AR ligands to improve affinity and selectivity profiles of adrenergic agonists. When bound to a full agonist, B2AR exhibits an 11‐Armstrong (A) protrusion of TM6 and inward folding of TM7 and TM3 to transform into a highly unstable arrangement that cannot be adequately established by the potential binding of a stronger agonist alone. The differences inside the ligand‐binding pocket are more subtle but exemplify the weakening of the polar interactions between the amino acids Asn293, Ser203, and Ser207. Once B2AR is activated by any partial or positive agonist, the detached stimulatory G‐protein catalyzes the activity of adenylyl cyclase. In turn, the intracellular cyclic adenosine monophosphate (cAMP) content is elevated significantly. cAMP initiates simultaneous pathways that aid in the release of constricted airways of bronchospastic patients. The pathways induced by the B2AR receptor therapeutically target muscle cell contraction, uterine relaxation, and premature labor within tocolytic drug candidates. Alternatively, B2AR functioning can be restrained by antagonists to inhibit basal, agonist‐independent activity that can be fatally detrimental, such as the continual production of glucose from glycogenolysis. The methodological advances to discover ligands that can function as inverse agonists through the crystallogenesis of B2AR proves to create promising drug treatments for cardiopulmo