Beta-Adrenergic Agonists

Abstract

Inhaled β₂-adrenoceptor (β₂-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β₂-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β₂-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β₂-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

Keywords: G-protein-coupled receptor signaling; airway smooth muscle; bronchodilation; desensitization; safety issues; β2-adrenoceptors.

Figure 1

Pre- and post-junctional intracellular mechanisms modulating cholinergic neurotransmission and airway smooth muscle (ASM) cell tone. At pre-junctional level, stimulation of β₂-adrenoceptor (β₂-AR) by agonists opens Ca²⁺-activated K⁺ (BKCa) channels leading to cell membrane hyperpolarization and reduction of acetylcholine (ACh) release. By contrast, direct activation of adenylyl cyclase (AC) enhances ACh release. In the ASM cell, stimulation of β₂-AR as well as direct stimulation of AC, opens BKCa channels determining cell membrane hyperpolarization and relaxation. The ACh released by postganglionic cholinergic nerves binds M₂-muscarinic receptors expressed both at pre- and post-junctional level, thus inhibiting ACh release and increasing ASM cell tone. cAMP: cyclic 3',5'-adenosine monophosphate; ATP: adenosine trisphosphate; G_s and G_i: stimulatory and inhibitory subunits of the receptor-coupled G-protein, respectively.

Figure 2

Mechanisms of relaxation and β₂-adrenoceptor (β₂-AR) desensitization in airway smooth muscle (ASM). The binding of a specific agonist to β₂-AR stimulates the receptor-coupled G_s-protein, which activates adenylyl cyclase (AC). The resulting increase of cyclic 3',5'-adenosine monophosphate (cAMP) activates protein kinase A (PKA), which phosphorylates inositol 1,4,5-trisphosphate receptor (IP₃R) of sarcoplasmic reticulum (SR) and opens Ca²⁺-activated K⁺ (BKCa) channels, thus leading to relaxation. However, activated PKA phosphorylates β₂-AR, uncoupling it from G_s-protein. Exposure of sensitized mast-cells to allergen causes release of leukotrienes (LT). Their interaction with the specific receptor, i.e., LT-R, activates a G_q-protein, which increases phospholipase C (PLC) activity. PLC catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂), which produces IP₃ and diacylglycerol (DAG). IP₃ leads to contraction by increasing release of Ca²⁺ from SR while DAG activates protein kinase C (PKC). The latter phosphorylates several substrates like calponin and CPI-17, which is an inhibitor of myosin-light-chain phosphatase (MLCP). In addition, PKC phosphorylates both β₂-AR and G_s-protein. A similar cascade of events seems to occur in response to acetylcholine (ACh) released by cholinergic nerves through M₃-muscarinic receptors. In addition, activation of M₂-muscarinic receptors inhibits AC, thus decreasing cAMP level and PKA activity. ATP: adenosine trisphosphate;: phosphorylation sites.