Adrenaline 32-adrenergic receptor binding

The adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors, which are the targets of catecholamines. Adrenergic receptors specifically bind their endogenous ligands, the catecholamines, epinephrine, and norepinephrine (also called adrenaline and noradrenaline), and are activated by these. 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

The switch for the activation of an intracellular signaling pathway is in most cases an increase in the concentration of the freely circulating hormone. This leads to an increase in the concentration of the hormone-receptor complex, which results in an increased activation of subsequent reactions in the cell. The concentration of the circulating hormone is thus the main regulatory parameter in cellular conummication. The relation between hormone concentration, binding of the hormone to the receptor, and subsequent reaction in the cell is illustrated in fig. 3.7 for the case of adrenaline and the P-adrenergic receptor. 

Fig. 5.6. Topology of the P-adrenergic receptor of hamster. The primary structure is shown of the P-receptor for adrenaline from hamster, with the assumed topology of the seven transmembrane helices. The extracellular domain is shown at the top of the picture. The interface of the ceU membrane is indicated by the dashed line. The filled squares show glycosylation sites. Amino adds not required for ligand binding, according to mutagenesis studies, are shown as open squares. Reprinted with permission of the American Journal of Respiratory Cell and Molecular Biology (1989), 1, No.2, p.82.

The interaction of the Pycomplex with G-protein coupled receptor kinases (see 5.3.4, P-adrenergic receptor kinase, PARK) appears to be of special regulatory importance. The function of the Py-complex in this system is shown in Fig. 5.9. The Py-complex binds specifically to the PARK and translocates this to the cell membrane. The translocation of PARK is necessary to switch off and modulate signal transmission via adrenaline. 

Receptor proteins (serpentine receptors) that indirectly activate (through GTP-binding proteins, or G proteins) enzymes that generate intracellular second messengers. This is illustrated by the /3-adrenergic receptor system that detects epinephrine (adrenaline) (Section 12.4). 

Sites that bind adrenaline (epinephrine), noradrenaline (norepinephrine), and related catecholamines (see Chapter 30) to almost all cell surfaces are classified as either a adrenergic or (5 adrenergic receptors. The P receptors, which have been studied the most,150 occur as two major types. 

The combination of norephedrine with caffeine works synergistically to drastically increase the body s production of adrenaline and noradrenaline-the primary adrenergic hormones. These hormones bind to the various adrenergic receptors, of which there are the beta sub 2, beta sub 3, and alpha sub 2 receptors, that together affect fat loss and fat dispersal. The stimulation of the beta sub 2 and the beta sub 3 receptors in particular is what s responsible for the mobilization and burning of adipose tissue (fat). These are the receptors that you want to stimulate to affect fat loss in a positive way and thankfully the caffeine/norephedrine combination is quite efficient at this. 

The major mechanism for the homologous desensitization of agonist-bound 7-helix transmembrane receptors consists of a two-step process in which the agonist-bound receptor is phosphorylated by a GRK and then binds an arrestin protein which interrupts signaling to the G protein. Well-characterized GRKs (review Pitcher et al., 1998) are those for rhodopsin, rhodopsin kinase and the fil adrenaline receptor, the -adrenergic receptor kinase (/ ARK).The GRKs are protein kinases thatare... 

Table 5. Examples of Alkaloids Which Bind to Adrenergic Receptors (Natural Ligand Noradrenaline, Adrenaline)...

The agonist isoproterenol is used to treat asthma, because it mimics the effects of catecholamines in relaxing bronchial muscles in the lung it does so by interacting with one specific class of adrenergic receptors (so-called because they bind adrenaline, the old name for epinephrine). 

---