Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intracellular and Intercellular Communication
Adrenal Medullary Hormones
Classification and Mechanism of Action of Catecholamines

Classification

The MECHANISM OF ACTION of catecholamines has captured the interest of researchers for nearly a century. Indeed, many General Concepts in receptor biology and hormone action trace their origins back to these earliest investigations.

Catecholamines act through two Major Classes of receptors: a-adrenergic and ß-adrenergic. Each of these is further divided into two subclasses: a₁ and a₂, and ß₁ and ß₂, respectively. This classification is based on the relative binding affinity for various Agonists and Antagonists. Epinephrine binds to (and activates) both a- and ß-receptors; consequently, its effect on a tissue containing both classes of receptors depends on the relative affinities of these receptors for the hormone. At physiological concentrations, norepinephrine binds primarily to a-receptors.

ß-Adrenergic Receptor

Molecular cloning of the mammalian ß-adrenergic receptor Gene and cDNA revealed unexpected features. First, the gene lacks introns, making it, along with histone and interferon genes, one of the rare groups of mammalian genes devoid of these structures. Second, the ß-adrenergic receptor shows close Homology with rhodopsin—at least across three peptide segments—the protein that initiates the visual response to light.

Class="center">Table 49.2. Effects mediated by various adrenergic receptors

Mechanism of Action

Receptors in three of these subgroups are coupled to the adenylate cyclase system. Hormones binding to ß₁- and β₂-receptors activate adenylate cyclase, whereas those associating with a₂-receptors inhibit it (see Fig. 44.3 and Table 44.3). Catecholamine binding induces the association of the receptor with a G protein, which subsequently binds GTP. This either stimulates (G_s) or inhibits (G_i) adenylate cyclase, ultimately leading to an increase or decrease in cAMP synthesis. The response is terminated when a GTPase associated with the a-subunit of the G protein hydrolyzes the GTP (see Fig. 44.2). a₁-Receptors participate in pathways leading to changes in intracellular calcium concentration or alterations in phosphatidylinositol METABOLISM (or both). It is likely that a specialized G-protein complex is required for this reaction.

A striking functional similarity exists between the catecholamine receptor and the visual Transduction system. Upon light stimulation, rhodopsin couples with Transducin, a G-protein complex whose a-subunit also binds GTP. The activated G protein, in turn, stimulates a phosphodiesterase that hydrolyzes cGMP. As a result, Ion Channels in the retinal cone Cell membranes close, generating the visual response. This process is switched off when the GTPase associated with the a-subunit hydrolyzes the bound GTP. A partial list of the biochemical and physiological effects mediated by various adrenergic receptors is provided in Table 49.2.

The activation of Phosphoproteins by cAMP-dependent protein kinase (see Fig. 44.4) accounts for many of the biochemical effects of epinephrine. In muscle and, to a lesser extent, in the Liver, epinephrine stimulates glycogenolysis by activating a protein kinase, which in turn triggers the phosphorylase cascade (see Fig. 19.7). Conversely, phosphorylation of Glycogen synthase dampens glycogen synthesis. Acting on The Heart, epinephrine increases Cardiac Output by enhancing both the force (inotropic effect) and frequency (chronotropic effect) of contractions, responses also linked to elevated cAMP levels. In adipose tissue, epinephrine raises cAMP content, which converts hormone-sensitive lipase into its active (phosphorylated) form. This enzyme accelerates lipolysis and the release of Fatty acids into the bloodstream. These fatty acids serve as an energy source for Muscles and can further stimulate hepatic gluconeogenesis.