β-receptors are membrane-bound receptors coupled to G-proteins. Three types of β-receptors have been identified by molecular pharmacology. β receptors make up to 75% of all beta receptors and are predominantly located in the heart. β receptors are found in vascular and bronchial smooth muscle. β receptors, which are presumed to be involved in fatty acid metabolism, are located in the adipocytes.
G-protein coupled receptors consist of single polypeptide chains of 300-600 amino acids and span the plasma membrane seven times. There are three extracellular loops, one of them being the amino-terminus, and three intracellular loops with a carboxy-terminus. The hydrophilic pocket is formed within the membrane by the seven alpha-helical transmembrane domains. The ligand binds to the hydrophilic pocket in the receptor protein and activates the receptor, giving rise to the cellular effect.
When the β-agonist binds and activates the β-adrenoreceptor intracellular signaling becomes largely affected through cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). The coupling of the β-receptor to adenylate cyclase is affected through a trimeric Gs protein, as shown in figure 2, consisting of an α-subunit (which stimulates adenylate cyclase) and βγ-subunits (which transduce other signals). Adenylate cyclase catalyzes the conversion of adenosine triphosphate into cAMP, which is a second messenger, thereby increasing the intracellular cAMP levels, resulting in relaxation of smooth muscles. cAMP levels are regulated through the activity of phosphodiesterase isozymes/isoforms, which degrades it to 5′-AMP.
The mechanism by which cAMP induces relaxation in airway smooth muscle cells is not fully understood. It is believed that cAMP catalyzes the activation of PKA, which in turn phosphorylates key regulatory proteins involved in the control of muscle tone. cAMP also has a role in inhibition of calcium ion (Ca) release from intracellular stores, sequestration of intracellular Ca, and reduction of membrane Ca entry, leading to relaxation of the airway smooth muscle.
The binding of norephinephrine to the binding site consists of one ionic bond, three hydrogen bonds and van der Waals interaction in two places. Ionic bonding forms between the protonated amine and Asp-113 in helix 3. Hydrogen bonds are formed from the hydroxyl groups, linked to the catechol ring, to Ser-204 and Ser-207 in helix 5. This binding limits configurational and rotational freedom. Van der Waals forces between aromatic catechol ring and Phe-290 in helix 6 residue and Val-114 in helix 3 residue reinforce the binding. It is believed that the N-alkyl substituents fit into a hydrophobic pocket formed between residues in helix 6 and 7. The beta-carbon is chiral and must have the R-configuration so that the beta-hydroxyl group is oriented towards the Asn-293 residue in helix 6 to form a hydrogen bond essential to binding to the beta-2 receptor.