Receptor Activation and Signaling

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The p2-adrenoreceptor is a G-protein coupled receptor, with seven transmembrane domains that are connected by intra- and extracellular connecting loops (Fig. 1). It has an extracellular amino terminus and an intracellular carboxyl terminus. The binding sites for ligands lie within the lipophilic transmembrane domains of the receptor. Amino acid residues that are directly involved in binding have been identified, e.g., asp 113, serine 204, and serine 207 (4). It is likely that ligands with different molecular structures can interact with different amino acid residues within the p2-AR binding site, and this contributes to variations in the pharmacological properties of ligands (5).

The activated p2-AR binds to cytoplasmic G-proteins (Fig. 2); this coupling process requires several molecular interactions between the intracellular portions of the receptor and G-protein (6). The p2-AR/G-protein complex activates the enzyme adenyl cyclase, which is responsible for the conversion of ATP to cAMP. This activates protein kinase A, which is able to phosphorylate proteins that are directly involved in the regulation of smooth muscle tone. Additionally, intracellular Ca levels are reduced through a variety of mechanisms. This also contributes to smooth muscle relaxation. There is also evidence that the activated p2-AR/G-protein complex interacts with cell membrane K channels (7).

For many years p2-AR and their ligands were thought to interact by a ''lock and key'' mechanism (Fig. 3A), with agonists that are a suitable shape (''the key'') binding to the receptor (''the lock''). This interaction was thought to cause a conformational change in the receptor that was required for effective G-protein coupling. This mechanism was postulated to be a simple ''on-off'' switch, as there was no receptor activity without an agonist present. As antagonists were thought to act by blocking the agonist-binding site, then agonists and antagonists ''competed'' for the same receptor molecules (Fig. 3B).

Gumg Transmembrane
Figure 1 p2-Adrenoreceptor structure. Transmembrane domains are connected by intra- and extracellular loops. Ligand binding is within the transmembrane domains. Source: From Ref. 3.

Figure 2 b2-Adrenoreceptor (b2-AR) signaling pathways. Agonist binding causes receptor coupling to G-proteins (G-P), which increases adenylate cyclase (A-C) conversion of ATP to cAMP. This activates protein kinase A (PKA), leading to smooth muscle relaxation. The b2-AR/G-P complex also interacts with potassium channels.

Figure 2 b2-Adrenoreceptor (b2-AR) signaling pathways. Agonist binding causes receptor coupling to G-proteins (G-P), which increases adenylate cyclase (A-C) conversion of ATP to cAMP. This activates protein kinase A (PKA), leading to smooth muscle relaxation. The b2-AR/G-P complex also interacts with potassium channels.

It now appears that the ''lock and key'' theory was too simplistic, as the p2-AR is in a state of constant equilibrium between activated and inactivated forms even when there are no ligands present (8,9) (Fig. 4A). The resting equilibrium favors the inactivated form, with only a minority of receptors being active at any given moment. This results in a low-basal level of b2-AR signaling through G-protein coupling in the absence of agonist binding. b2-agonists bind to the activated form and stop conversion back to the inactive form (Fig. 4B). This shifts the equilibrium toward the active form, causing increased b2-AR signal transduction. In contrast, b2-antagonists bind and stabilize the inactivated form, thus shifting the equilibrium away from the active form. It therefore appears that agonists and antagonists bind to different forms of the p2-AR. Furthermore, the p2-AR may exist in equilibrium between many different conformations, each with different levels of signal transduction activity. Partial agonists are either less able to stabilize active conformations, or are specific for conformations with lower basal levels of signal transduction activity compared to full agonists.

Traditionally, the pharmacological effectiveness of b2-agonists in asthma have been related to the following three factors; local concentration

Figure 3 The ''lock and key'' receptor theory. (A) Agonists have a suitable molecular conformation for receptor binding. (B) Antagonists ''compete'' for the same binding sites.

Figure 4 The dynamic model of b2-adrenoreceptor-ligand interactions. (A) The receptor is in a resting equilibrium that favors an inactive isoform. There is a low-basal level of activity due to the active isoform. (B) Agonist binding stabilizes the active isoform, which is now not in equilibrium. This increases the total number of active receptors, so increasing b2-adrenoreceptor signaling.

Figure 4 The dynamic model of b2-adrenoreceptor-ligand interactions. (A) The receptor is in a resting equilibrium that favors an inactive isoform. There is a low-basal level of activity due to the active isoform. (B) Agonist binding stabilizes the active isoform, which is now not in equilibrium. This increases the total number of active receptors, so increasing b2-adrenoreceptor signaling.

in the lungs, receptor binding affinity, and intrinsic activity. The local concentration is determined by inhaler device characteristics, inhaled particle mass, and lipophilicity. Binding affinity refers to the ability of the ligand to bind to the receptor, while intrinsic activity refers to the degree of stimulation of the receptor due to conformational shape change. Local concentration and binding affinity are undoubtedly of importance in determining the pharmacological effects of inhaled p-agonists. However, the theory of intrinsic activity assumes that p-agonists exert their actions through the ''lock and key'' mechanism. This theory has now been superceded by evidence that the ability of p-agonists to stabilize active p2-AR isoforms is an important determinant of pharmacological activity.

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