α- and β-Adrenergic Receptor Subtypes

Research paper by Perry B. Molinoff

Indexed on: 12 Oct '12Published on: 12 Oct '12Published in: Drugs


The effects of catecholamines in the central and peripheral nervous systems appear to be mediated through interactions with 2 major classes of receptor: α-adrenoceptors and β-adrenoceptors. Subtypes of both α- and β-adrenoceptors exist. In the periphery, α1-receptors are located postsynaptically, mediating the excitatory effects of catecholamines at α-receptors. α2-Adrenoceptors, on the other hand, are autoreceptors involved in the regulation of noradrenaline (norepinephrine) release. In the central nervous system, both α1- and α2-receptors exist on postsynaptic cells; there are also 2 principal subtypes of β-adrenoceptors. β1-Receptors have a high affinity for both noradrenaline and adrenaline (epinephrine) and are found in the heart, brain, and adipose tissue. β2-Receptors have a low affinity for noradrenaline and are involved in mediation of relaxation of vascular and other smooth muscles and in many of the metabolic effects of catecholamines.A variety of effector systems have been implicated in the actions of catecholamines. Most, though not all, of the effects of catecholamines at β-receptors are mediated through activation of adenyl cyclase and increases in cyclic AMP accumulation. The effects of catecholamines at α-receptors generally involve other second messenger systems. Thus, in at least some systems, stimulation of α1-adrenoceptors mediates increases in phosphoinositide breakdown, while α2-adrenoceptors appear to act through inhibition of adenyl cyclase activity.The pharmacological effects of α- and β-adrenoceptors were initially characterised by measuring responses observed in intact preparations. The advent of the use of radioligand binding techniques has allowed direct approaches to the characterisation of receptor properties. The use of radioligands makes it possible to determine the affinities of receptors for specific ligands, and it is possible to determine the density of receptors in a tissue. Finally, in vitro assays serve as a means through which receptors can be followed during solubilisation, isolation, and reconstitution.Several ligands are now available for the study of α- and β-adrenoceptors. In general, relatively selective radioligands are available for the study of α-receptors. Thus, 3H-WB 4101 and 3H-prazosin are selective ligands for α1-receptors; the ligand 125I-IBE 2254 also shows high selectivity for α1-receptors. 3H-Yohimbine and 3H-rauwolscine are selective antagonists for the labelling of α2-receptors and 3H-clonidine is a selective agonist used for studying α2-receptors. Most of the radioligands available for the study of β-adrenoceptors are nonselective, in that both β1- and β2-receptors have the same affinity for these ligands. The most widely used are the antagonists 3H-dihydroalprenolol and 125I-iodopindolol. The agonist 3H-hydroxybenzylisoprenaline is a useful ligand which shows some selectivity for β2-compared with β1-receptors.It is possible to use radioligands to study receptor subtypes quantitatively. In the case of α-receptors, where the radioligands are themselves selective, saturation curves followed by Scatchard analysis provide an estimate of the density and properties of a specific subtype of α-adrenoceptor. With β-receptor subtypes, the usual approach is to label all of the classes of receptors in a given tissue and then to inhibit selectively the binding of the radioligand with a highly selective competing ligand. Studies of receptor subtypes have revealed that in many cases multiple receptor subtypes coexist in the same tissue. In the central nervous system, receptor subtypes are independently regulated and heterogeneously distributed. In particular, manipulations which affect neuronal activity in rat cerebral cortex lead to apparently compensatory changes in the density of β1-adrenoceptors without any effect on the density of β2-receptors. These results led to the conclusion that β1-receptors are associated with neurons, while β2-receptors are associated with more homogeneously distributed tissue elements such as glia or blood vessels. The heart contains both β1- and β2-adrenoceptors and both subtypes are involved in mediating the effects of catecholamines on the heart.The effects of prolonged administration of agonists and antagonists on the density of receptors in human circulating lymphocytes have been investigated. Administration of an antagonist such as propranolol led to an increase in the density of receptors, which may account for the delayed hypersensitivity observed after abrupt discontinuation of propranolol. In similar experiments in which the agonists ephedrine and terbutaline were administered long term to normal volunteers, there was a decrease in the density of receptors. This could explain any loss of efficacy observed during long term therapy with sympathomimetic agents.