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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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α- and β-Adrenergic Receptors

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The pharmacological responses to catecholamines were ascribed to effects of α- and β-adrenergic receptors in the late 1940s

NE and epinephrine act at both α and β receptors, but isoproterenol, a synthetic agonist, acts only at β receptors (Tables 12-412-6). Numerous antagonists also differentiate between α and β receptors. The prototypic β-adrenergic receptor antagonist propranolol is essentially inactive at α receptors; the α-adrenergic receptor antagonist phentolamine is very weak at β receptors.

Distinct subtypes of β-adrenergic receptor exist and have important pharmacological consequences. β1-Adrenergic receptors predominate in the heart and in the cerebral cortex, whereas β2-adrenergic receptors predominate in the lung and cerebellum. However, in many cases, β1- and β2-adrenergic receptors coexist in the same tissue, sometimes mediating the same physiological effect. A major side effect of β2-selective agonists like metaproterenol, used to treat bronchial asthma, is cardiac acceleration. This is due to the coexistence of β1- and β2-adrenergic receptors in the heart. Both classes of receptor are coupled to the electrophysiological effects of catecholamines in the heart.

The brain contains both β1 and β2 receptors, which cannot be differentiated in terms of their physiological functions. Moreover, radioactive drugs that bind exclusively to one or the other type of β receptor are not yet available. However, one can label all of the β-adrenergic receptors in a given tissue with a nonselective radioligand and then selectively inhibit binding to one of the β-receptor subtypes with increasing concentrations of β1- or β2-selective agents [21]. ICI 89,406 and ICI 118,551 are highly selective antagonists at β1- and β2-adrenergic receptors, respectively. A similar approach can be used to define the anatomical localization of β1- and β2-adrenergic receptors using the technique of quantitative autoradiography. The density of β1 receptors varies in different brain areas to a greater extent than does that of β2 receptors. It has been suggested that this is due to the presence of β2-adrenergic receptors on glia or blood vessels.

A third subtype of β-adrenergic receptor has been identified. This receptor has pharmacological properties distinct from those of β1- and β2-adrenergic receptors. Agonists that are selective for β3 receptors exist and cause nonshivering thermogenesis in rodents. The β3 receptor in humans has been linked to hereditary obesity, control of lipid metabolism and the development of diabetes. mRNA for β3-adrenergic receptors is selectively expressed in brown adipose tissue present in rodents and in newborn humans. Message can be detected in white adipose tissue, but expression is very low.

The amino acid sequences of β-adrenergic receptors in brain and various tissues have been determined

A striking structural feature of the β-adrenergic receptors that have been cloned and sequenced, from turkey erythrocytes, hamster lung and human placenta and brain, and of the other members of the G protein-linked receptor family is their topographical orientation with respect to the membrane [23,24] (see Fig. 12-4). Hydropathicity analysis suggests that there are seven hydrophobic regions, each of 20 to 25 amino acids. These are potentially membrane-spanning. Other structural features of β-adrenergic receptors include a long C-terminal hydrophilic sequence thought to be intracellular, a somewhat shorter N-terminal hydrophilic sequence thought to be extracellular and a long cytoplasmic loop between presumptive transmembrane segments V and VI. Sites for N-linked glycosylation are found in the N-terminal extracellular portion of the molecule, while numerous sites that may be phosphorylated are found in the C-terminal portion of the molecule and on the i2 and i3 loops (see Chap. 22). Evidence from studies involving limited proteolysis and site-directed mutagenesis has led to the conclusion that the hydrophobic transmembrane helices are involved in the formation of the binding site for catecholamines, and the i3 loop together with the C terminus may play a role in the interaction of the receptor with GTP-binding proteins (see Chap. 20). A conserved aspartate residue in transmembrane 3 and a pair of serines in transmembrane 5 are thought to provide counter-ions for the amino and catechol hydroxyl groups, respectively [24].

Multiple serine and threonine residues on the i3 loop and C terminus and consensus sequences for cAMP-dependent phosphorylation may be important in explaining processes including agonist-induced receptor sequestration and desensitization (see also below). cAMP- and non-cAMP-dependent phosphorylations of β-adrenergic receptors have been observed. β-adrenergic receptor-stimulated synthesis of cAMP results in activation of PKA. The phosphorylated receptor is functionally uncoupled. Other receptors coupled to activation of adenylyl cyclase can also cause what is known as heterologous desensitization. In addition, occupancy of β-adrenergic receptors by agonists results in the activation of β-adrenergic receptor kinase (βARK), which leads to phosphorylation of the receptor. The uncoupling of the receptor from Gs also appears to involve a protein called β-arrestin, which is similar to a 48-kDa protein in the retina (see Chap. 47).

The proposed structure of the β-adrenergic receptor is strikingly similar in sequence and topography to that of bacterial rhodopsin (see Chap. 47) and the other members of the G protein-linked receptor family whose cDNAs have recently been cloned (see Chap. 20). Although these proteins mediate widely disparate biological effects, they show a high degree of homology. This is almost certainly related to the fact that, in each case, the immediate consequence of receptor activation is to promote an interaction between the receptor and a GTP-binding protein. The homologies between the members of the extended family of proteins are most evident within the presumed membrane-spanning helices.

Two families of α-adrenergic receptors exist

Radiolabeled agonists and antagonists have been used to label α receptors in both the brain and the peripheral tissues. As with β receptors, the binding properties of α receptors are essentially the same in the brain and the periphery. Some tissues possess only postsynaptic α1 receptors, others postsynaptic α2 receptors, and some organs have a mixture of both. Results of pharmacological and physiological studies have led to the suggestion that there are multiple types of α1 and α2 receptors. Of particular clinical importance are differences in the properties of junctional and extrajunctional α receptors. The proportions of α1 and α2 receptors also vary in different brain regions [25,26]. The physiological consequences of the two types of α receptor in the brain are unclear at the present time. It is striking that the drug specificity of postsynaptic α2 receptors closely resembles that of adrenergic autoreceptors, which are therefore also referred to as α2 receptors.

Studies involving the binding of radioligands are also consistent with the suggestion that there are subtypes of both α1- and α2-adrenergic receptors (Tables 12-4 and 12-5). The suggestion that there are subtypes of α1-adrenergic receptor was initially based on a comparison of the properties of [3H]prazosin and [3H]WB4-101 binding to α1-adrenergic receptors in rat brain and uterus. Heterogeneity of α2-adrenergic receptors was initially based on a comparison between the binding of [3H]clonidine and [3H]yohimbine in a variety of tissues and species. The observation that prazosin is more potent in neonatal rat lung [25,26] and cerebral cortex than in the human platelet, the prototypic tissue for the study of α2 receptors, was interpreted as indicating a heterogeneity in the pharmacological characteristics of α2-adrenergic receptors. Cloning and sequence analysis suggest that there are three subtypes of α1-adrenergic receptor and three subtypes of α2-adrenergic receptor [26,27]. In some instances, the α1D receptor has been linked to activation of Ca2+ channels, while the α1B receptor has been shown to activate phosphoinositide-specific phospholipase C (PI-PLC), resulting in liberation of diacylglycerol (DAG) and inositol trisphosphate (IP3) (see Chap. 20). Prototypic tissues expressing each of the subtypes of α2 receptor have been identified. All three of the known subtypes of α2-adrenergic receptor are linked to inhibition of adenylyl cyclase activity. As seen with other receptors linked to inhibition of adenylyl cyclase activity, the α2-adrenergic receptors have long i3 loops and relatively short C-terminal tails.

Not surprisingly, the known subtypes of α-adrenergic receptor share structural features with DA receptors (Fig. 12-4) and the other members of the G protein-linked receptor family. The degree of sequence identity is greater when the subtypes of α1 or α2 receptors are compared with each other than when α1 and α2 receptors are compared. The sequences of α1 and α2 receptors are not more closely related to each other than either is to the three known members of the β-adrenergic receptor family. Nomenclature notwithstanding, it is appropriate to think of three families of adrenergic receptor called α1, α2 and β. Sequence similarities both within and between families of adrenergic receptors are greater when the sequences of the putative transmembrane helices are compared than when one looks at overall sequence identity. It is sometimes difficult to distinguish between receptor subtypes and species homologs of the same receptor. Small differences in amino acid sequence can sometimes lead to large changes in the pharmacological specificity of an expressed receptor. The possibility that additional catecholamine receptors remain to be identified clearly exists.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28138

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