α and β-adrenergic receptors (2023)

Pharmacological responses to catecholamines attributed to the action of α and β-adrenergic receptors in the late 1940s

NOand epinephrine act on both α and β receptors, but isoproterenol, a synthetic agonist, acts only on β receptors (Tables 12-4–12-6). Many antagonists also differentiate between α and β receptors. The original β-adrenergic receptor antagonist, propranolol, is essentially inactive at α-receptors. The α-adrenergic receptor antagonist, phentolamine, has a very weak β-receptor effect.

There are distinct subtypes of β-adrenergic receptors that have important pharmacological consequences. b₁Adrenergic receptors dominate in the heart and cerebral cortex, while b.₂Adrenergic receptors are predominant in the lungs and cerebellum. However, in many cases b₁- and b₂- adrenergic receptors coexist in the same tissue, sometimes mediating the same physiological effect. Main side effect b₂-Selective agonists, such as metaproterenol, used to treat bronchial asthma, are drugs that increase the heart rate. This is due to the coexistence of b₁- and b₂-adrenergic receptors in the heart. Both classes of receptors are related to the electrophysiological effects of catecholamines on the heart.

The brain contains both b₁and b₂receptors that cannot be differentiated in terms of physiological functions. Furthermore, radioactive drugs that exclusively bind to one or the other type of β receptor are not yet available. However, it is possible to label all β-adrenergic receptors in a given tissue with a non-selective radioligand and then selectively inhibit binding to one of the β-receptor subtypes as the concentration of β-adrenergic increases.₁- the b₂-selective measures [21] ICI 89,406 and ICI 118,551 are highly selective β-antagonists₁- and b₂- adrenergic receptors, respectively. A similar approach can be used to determine the anatomical location of b₁- and b₂-adrenergic receptors by quantitative autoradiography. density b₁Receptors vary in different areas of the brain to a greater extent than in b₂receptors. It has been suggested that this is due to the presence of b₂- adrenergic receptors in glia or blood vessels.

A third subtype of β-adrenergic receptor has been identified. This receptor has pharmacological properties different from the β receptor₁- and b₂- adrenergic receptors. Players who are selective for b₃receptors are present and induce non-shivering thermogenesis in rodents. letter B₃the receptor in humans has been linked to hereditary obesity, control of lipid metabolism, and the development of diabetes.mRNAfor b₃- Adrenergic receptors are selectively expressed in brown adipose tissue found in rodents and neonates. The message can be detected in white adipose tissue, but expression is very low.

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

A striking structural feature of the cloned and sequenced β-adrenergic receptors from turkey erythrocytes, hamster lung, and human placenta and brain, as well as other members of the G protein-coupled receptor family, is their topographic orientation relative to the membrane.23,24] (I seeDig. 12-4). Hydropathy analysis suggests that there are seven hydrophobic regions, each 20 to 25 amino acids long. These are membrane potentials. Other structural features of β-adrenergic receptors include a long C-terminal hydrophilic sequence believed to be intracellular, a slightly shorter N-terminal hydrophilic sequence believed to be extracellular, and a long cytoplasmic loop between the putative transmembrane segments V and VI. Websites forNLinked glycosylation is found in the N-terminal extracellular portion of the molecule, while numerous phosphorylation sites are found in the C-terminal portion of the molecule and₂Me too₃loops (see chapter 22). Evidence from studies involving limited proteolysis and site-directed mutagenesis has led to the conclusion that hydrophobic transmembrane helices are involved in the formation of the catecholamine binding site and₃The loop along with the C-terminus may play a role in receptor interactionGTP- binding proteins (see chapter 20). The conserved aspartate residue in transmembrane 3 and the serine pair in transmembrane 5 are thought to provide counterions for the catechol amino and hydroxyl groups, respectively [24]

Many serine and threonine residues in i₃loop and C-terminus and consensus sequencescampDependent phosphorylation may be important to explain processes including agonist-induced receptor sequestration and desensitization (see also below). Both cAMP-dependent and cAMP-independent phosphorylation of β-adrenergic receptors was observed. Stimulated by the β-adrenergic receptor, the synthesis of cAMP causes its activationPKA. The phosphorylated receptor is functionally dissociated. Other receptors associated with the activation of adenylyl cyclase can also cause so-called heterologous desensitization. In addition, occupancy of β-adrenergic receptors by agonists results in activation of β-adrenergic receptor kinase (VARC), leading to phosphorylation of the receptor. Receptor detachment from G_smallIt also seems to involve a protein called β-arrestin, which is similar to the 48 kDa protein in the retina (see Chapter 47).

The proposed structure of the β-adrenergic receptor is strikingly similar in sequence and topography to bacterial rhodopsin (see Chapter 47) and other members of the G protein-coupled receptor family whose cDNA has been recently cloned (see Chapter 20). . Although these proteins mediate very different biological effects, they show a high degree of homology. This is almost certainly due to the fact that in any case the direct consequence of receptor activation is the promotion of receptor-receptor interactions.GTP- binding protein. Homologies between members of the extended family of proteins are most evident in the putative helices extending across the membrane.

There are two families of α-adrenergic receptors

Radiolabeled agonists and antagonists have been used to label alpha receptors in both brain and peripheral tissues. As with β receptors, the binding properties of α receptors are essentially the same in the brain and in the periphery. Some tissues have only postsynaptic a₁receptors, other postsynaptic a₂receptors and some organs have a mixture of both. The results of pharmacological and physiological studies have led to the conclusion that there are many types of a₁i a₂receptors. Of particular clinical importance are the differences in the binding and non-binding properties of the α-receptors. A relations₁i a₂Receptors also differ in different areas of the brain [25,26] The physiological consequences of the two types of α receptors in the brain are currently unclear. It is striking that the healing specificity of postsynaptic a₂The receptors closely resemble those of the adrenergic autoreceptors, which are therefore also referred to as a₂receptors.

Radioligand binding studies are also consistent with the proposal that there are subtypes of both a₁- i₂- adrenergic receptors (Tables 12-4I12-5). The theorem that there are subtypes a₁- the adrenergic receptor was originally based on a comparison of the properties of [³H]prazosyna i [³H]WB4-101 binding to a₁-adrenergic receptors in the rat brain and uterus. Heterogeneity a₂-adrenergic receptors were initially based on a binding comparison of [³H]klonidyna i [³H]yohimbine in various tissues and species. Observation that prazosin is more potent in neonatal rat lungs [25,26] and cerebral cortex than in human platelets, a prototype tissue to study a₂receptors, was interpreted as indicating heterogeneity in pharmacological properties a₂- adrenergic receptors. Cloning and sequence analysis suggest that there are three subtypes of a₁- adrenergic receptor and three subtypes a₂-adrenergic receptor [26,27] In some cases, A_1Dthe receptor has been linked to Ca activation²+ channels while a_1BThe receptor has been shown to activate phosphoinositide phospholipase C (PI-PLC), which releases diacylglycerol (Day) i trifosforan inozytolu (IP3) (see chapter 20). Prototype tissues expressing each of the subtypes a₂receptors have been identified. All three known subtypes of a₂- the adrenergic receptor is associated with the inhibition of adenylyl cyclase activity. As seen with other receptors involved in inhibiting adenylate cyclase activity, a₂-adrenergic receptors are long₃loops and relatively short C-terminal tails.

Not surprisingly, the known subtypes of α-adrenergic receptors share structural featuresIreceptors (Dig. 12-4) and other members of the G protein-coupled receptor family. The degree of sequence identity is greater when the α subtypes₁the₂receptors are compared to each other than when a₁i a₂receptors are compared. A sequences₁i a₂The receptors are no more closely related to each other than to the three known members of the β-adrenergic receptor family. Despite the nomenclature, there are three families of adrenergic receptors to think about called a₁, A₂and b. Sequence similarities both within and between adrenergic receptor families are greater when comparing the sequences of putative transmembrane helices than when considering overall sequence identity. It is sometimes difficult to distinguish between receptor subtypes and homologous species of the same receptor. Small differences in amino acid sequence can sometimes lead to large changes in the pharmacological specificity of the expressed receptor. There is a clear possibility to identify additional catecholamine receptors.