There are three major types of adrenergic receptors, i.e., those receptors that bind the catecholamines epinephrine and norepinephrine. These are known as α1, α2, and β and were originally distinguished by their ligand (including agonists and antagonists) binding characteristics. More recent molecular studies have revealed that each of these groups is composed of three subtypes, each encoded by a separate gene. All of the adrenergic receptors are single polypeptide proteins with seven hydrophobic membrane-spanning regions and are members of the large class of G-protein coupled receptors. Some structural characteristics are shown in the top part of Figure 1. The receptor classes differ in sites of glycosylation on the external portion and in the sizes of the intracellular loop and carboxyl terminus. These structural differences undoubtedly are the basis for the differences in the ligand specificities of the receptors and in intracellular signaling mechanisms.
Fig2. Adrenergic receptors. The adrenergic receptors, which bind epinephrine and norepinephrine (as well as synthetic compounds such as those in Figure 1) are classified into three major groups, α1, α2, and β, based on pharmacological properties and type of signaling system. The features of these three groups are shown in this figure. The subtypes within each group are listed below the major example shown. All of the adrenergic receptors are G-protein coupled receptors (GPCRs) containing seven membrane-spanning regions. In the structural depictions of the receptors at the top, the approximate locations of extracellular N-glycosylation sites are shown (Y), as are the intracellular loop (green) and the carboxy terminal tail (magenta). The signaling systems are shown at the bottom of the figure, where the major Gα protein to which the receptor is coupled is indicated (tan circle) along with the primary enzymatic activity affected (PLC, phospholipase C; AC-adenyl cyclase) and the effect on the second messenger (increased ionized calcium, decreased or increased cyclic AMP).
Also shown in Figure 1 is the primary G-protein with which each subtype interacts, leading to the functional differences between the receptor subtypes. Thus, the intracellular signaling pathway of α1 adrenergic receptors is generally mediated by an increase in intra cellular Ca2+ levels; that of α2 receptors by decreased cyclic AMP; and that of the β receptors by increased cyclic AMP. Although these signaling pathways are characteristic of each of the receptor types, other path ways have been shown to be activated by each of them in certain cells and under certain conditions of, for example, ligand concentration. These other pathways include activation of K+ channels, activation or inhibition of Ca2+ channels, activation of phospholipase A2 for prostaglandin synthesis, and mitogen-activation protein kinase (MAPK).
Table 1 lists the approximate relative potencies of the adrenergic receptor subtypes for epinephrine and norepinephrine. The β3 receptor responds better to nor epinephrine than to epinephrine while the β2 receptor has a strong, about 10-fold, preference for epinephrine. The α1, α2, and β1 types are fairly nonselective between these two ligands. It should be noted that the receptor preferences indicated are apparent at low (subsaturating) concentrations of the ligands and may be different at higher concentrations of one or both of them.
Table1. Relative Ligand Specificity of Adrenergic Receptors
The β-adrenergic and most of the α-adrenergic receptors undergo desensitization through phosphorylation of the carboxy terminus and removal of the receptor from the membrane. This process, which is common to many GPCRs, involves G-protein coupled receptor kinase mediated phosphorylation of the receptor, rendering it capable of binding to β-arrestin followed by endocytosis. This process is one of several ways in which the signal initiated by epinephrine or norepinephrine is terminated in the target cell.
