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Chapter: Basic & Clinical Pharmacology : Adrenoceptor Agonists & Sympathomimetic Drugs

Molecular Pharmacology Underlying the Actions of Sympathomimetic Drugs

Molecular Pharmacology Underlying the Actions of Sympathomimetic Drugs
The effects of catecholamines are mediated by cell-surface receptors.



The effects of catecholamines are mediated by cell-surface receptors. Adrenoceptors are typical G protein-coupled receptors (GPCRs;). The receptor protein has an extracellular N-terminus, traverses the membrane seven times (transmembrane domains) forming three extracellular and three intracellular loops, and has an intracellular C-terminus (Figure 9–1). G proteincoupled receptors are coupled by G proteins to the various effec-tor proteins whose activities are regulated by those receptors. EachG protein is a heterotrimer consisting of α, β, and γ subunits. G proteins are classified on the basis of their distinctive α subunits. G proteins of particular importance for adrenoceptor function include Gs, the stimulatory G protein of adenylyl cyclase; Gi and Go, the inhibitory G proteins of adenylyl cyclase; and Gq and G11, the G proteins coupling α receptors to phospholipase C. The activation of G protein-coupled receptors by catecholamines pro-motes the dissociation of guanosine diphosphate (GDP) from thesubunit of the appropriate G protein. Guanosine triphosphate (GTP) then binds to this G protein, and the α subunit dissociates from the β-γ unit. The activated GTP-bound α subunit then regulates the activity of its effector. Effectors of adrenoceptor-activated α subunits include adenylyl cyclase, cGMP phosphodi-esterase, phospholipase C, and ion channels. The α subunit is inactivated by hydrolysis of the bound GTP to GDP and phos-phate, and the subsequent reassociation of the α subunit with the β-γ subunit. The β-γ subunits have additional independent effects,acting on a variety of effectors such as ion channels and enzymes.


Adrenoreceptors were initially characterized pharmacologically, with α receptors having the comparative potencies epinephrine norepinephrine >> isoproterenol, and β receptors having the com-parative potencies isoproterenol > epinephrine norepinephrine. The development of selective antagonists revealed the presence of subtypes of these receptors, which were finally characterized by molecular cloning. We now know that unique genes encode the receptor subtypes listed in Table 9–1.

Likewise, the endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors (Table 9–1). These receptors are dis-tinct from α and β receptors and are particularly important in the brain  and in the splanchnic and renal vasculature. Molecular cloning has identified several distinct genes encoding five receptor subtypes, two D1-like receptors (D1 and D5) and three D2-like (D2, D3, and D4). Further complexity occurs because of the presence of introns within the coding region of the D2-like receptor genes, which allows for alternative splicing of the exons in this major subtype. There is extensive polymorphic variation in the D4 human receptor gene. These subtypes may have importance for understanding the efficacy and adverse effects of novel antipsychotic drugs .

Receptor Types

A. Alpha Receptors

Alpha1 receptors are coupled via G proteins in the Gq family to phospholipase C. This enzyme hydrolyzes polyphosphoinositides, leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (Table 9–1, Figure 9–1). IP3promotes therelease of sequestered Ca2+ from intracellular stores, which increases the cytoplasmic concentration of free Ca2+ and the activation of various calcium-dependent protein kinases. Activation of these receptors may also increase influx of calcium across the cell’s plasma

membrane. IP3 is sequentially dephosphorylated, which ultimately leads to the formation of free inositol. DAG activates protein kinase C, which modulates activity of many signaling pathways. In addi-tion, α1 receptors activate signal transduction pathways that were originally described for peptide growth factor receptors that activate tyrosine kinases. For example, α1 receptors have been found to acti-vate mitogen-activated kinases (MAP kinases) and polyphospho-inositol-3-kinase (PI-3-kinase). These pathways may have importance for the α1-receptor–mediated stimulation of cell growth and proliferation through the regulation of gene expression.

Alpha2 receptors inhibit adenylyl cyclase activity and cause intracellular cyclic adenosine monophosphate (cAMP) levels to decrease. Alpha2-receptor–mediated inhibition of adenylyl cyclase activity is transduced by the inhibitory regulatory protein, Gi (Figure 9–2). It is likely that not only α, but also the β-γ subunits of Gi contribute to inhibition of adenylyl cyclase. Alpha2 receptors use other signaling pathways, including regulation of ion channel activities and the activities of important enzymes involved in sig-nal transduction. Indeed, some of the effects of α2 adrenoceptors are independent of their ability to inhibit adenylyl cyclase; for example, α2-receptor agonists cause platelet aggregation and a decrease in platelet cAMP levels, but it is not clear whether aggre-gation is the result of the decrease in cAMP or other mechanisms involving Gi-regulated effectors.

B. Beta Receptors

Activation of all three receptor subtypes (β1, β2, and β3) results in stimulation of adenylyl cyclase and increased conversion ofadenosine triphosphate (ATP) to cAMP (Table 9–1, Figure 9–2). Activation of the cyclase enzyme is mediated by the stimulatory coupling protein Gs. Cyclic AMP is the major second messenger of β-receptor activation. For example, in the liver of many species, β-receptor–activated cAMP synthesis leads to a cascade of eventsculminating in the activation of glycogen phosphorylase. In the heart, β-receptor–activated cAMP synthesis increases the influx of calcium across the cell membrane and its sequestration inside the cell. Beta-receptor activation also promotes the relaxation of smooth muscle. Although the mechanism of the smooth muscle effect is uncertain, it may involve the phosphorylation of myosin light-chain kinase to an inactive form (see Figure 12–1). Beta adrenoceptors may activate voltage-sensitive calcium channels in the heart via Gs-mediated enhancement independently of changes in cAMP concentration. Under certain circumstances, β2 recep-tors may couple to Gq proteins. These receptors have been dem-onstrated to activate additional kinases, such as MAP kinases, byforming multi-subunit complexes within cells, which contain multiple signaling molecules.

The β3 adrenoreceptor is a lower affinity receptor compared with β1 and β2 receptors but is more resistant to desensitization. It is found in several tissues, but its physiologic or pathologic role in humans is not clear. Selective agonists and antagonists have been developed but are not clinically available.

C. Dopamine Receptors

The D1 receptor is typically associated with the stimulation of adenylyl cyclase (Table 9–1); for example, D1-receptor–induced smooth muscle relaxation is presumably due to cAMP accumula-tion in the smooth muscle of those vascular beds in which dop-amine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx.

Receptor Selectivity

Many clinically available adrenergic agonists have selectivity for the major (α1 and α2 versus β) adrenoreceptor types, but not for the subtypes of these major groups. Examples of clinically useful sympathomimetic agonists that are relatively selective for α1-, α2-, and β-adrenoceptor subgroups are compared with some nonselec-tive agents in Table 9–2. Selectivity means that a drug may prefer-entially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup. However, selec-tivity is not usually absolute (nearly absolute selectivity has been termed “specificity”), and at higher concentrations, a drug may also interact with related classes of receptors. The effects of a given drug may depend not only on its selectivity to adrenoreceptor types, but also to the relative expression of receptor subtypes in a given tissue. (see Box: Receptor Selectivity and Physiologic Functions of Adrenoceptor Subtypes).

Receptor Regulation

Responses mediated by adrenoceptors are not fixed and static. The number and function of adrenoceptors on the cell surface and their responses may be regulated by catecholamines themselves, other hormones and drugs, age, and a number of disease states . These changes may modify the magnitude of a tissue’s physiologic response to catecholamines and can be important clinically during the course of treatment. One of the best-studied examples of receptor regulation is the desensitization of adreno-ceptors that may occur after exposure to catecholamines and other sympathomimetic drugs. After a cell or tissue has been exposed for a period of time to an agonist, that tissue often becomes less responsive to further stimulation by that agent (see Figure 2–12).

Receptor Selectivity and Physiologic Functions of Adrenoceptor Subtypes: Lessons from Knockout Mice

Since pharmacologic tools used to evaluate the function of adrenoceptor subtypes have some limitations, a number of knockout mice have been developed with one or more adre-noceptor genes subjected to loss of function mutations, as described (see Box: Pharmacology & Genetics). These models have their own complexities, and extrapola-tions from mice to humans may be uncertain. Nonetheless, these studies have yielded some novel insights. For example, α-adrenoceptor subtypes play an important role in cardiac responses, the α2A-adrenoceptor subtype is critical in trans-ducing the effects of α2 agonists on blood pressure control, and β1 receptors play a predominant role in directly increas-ing heart rate in the mouse heart.

Other terms such as tolerance, refractoriness, and tachyphylaxis have also been used to denote desensitization. This process has potential clinical significance because it may limit the therapeutic response to sympathomimetic agents.

Many mechanisms have been found to contribute to desensiti-zation. Some mechanisms function relatively slowly, over the course of hours or days, and these typically involve transcriptional or translational changes in the receptor protein level, or its migra-tion to the cell surface. Other mechanisms of desensitization occur quickly, within minutes. Rapid modulation of receptor function in desensitized cells may involve critical covalent modification of the receptor, especially by phosphorylation on specific amino acid residues, association of these receptors with other proteins, or changes in their subcellular location.

There are two major categories of desensitization of responses mediated by G protein-coupled receptors. Homologous desensi-tization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist. Heterologous desensitization refers to the process by which desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly acti-vated by the agonist in question.

A major mechanism of desensitization that occurs rapidly involves phosphorylation of receptors by members of the G protein-coupled receptor kinase (GRK) family, of which there are sevenmembers. Specific adrenoceptors become substrates for these kinases only when they are bound to an agonist. This mechanism is an example of homologous desensitization because it specifically involves only agonist-occupied receptors.


Phosphorylation of these receptors enhances their affinity for arrestins, a family of four widely expressed proteins. Upon binding of arrestin, the capacity of the receptor to activate G proteins is blunted, presumably as a result of steric hindrance(see Figure 2–12). Arrestin then interacts with clathrin and clathrin adaptor AP2, leading to endocytosis of the receptor. In addition to blunting responses requiring the presence of the receptor on the cell surface, these regulatory processes may also contribute to novel mechanisms of receptor signaling via intra-cellular pathways.

Receptor desensitization may also be mediated by second-messenger feedback. For example, β adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A; protein kinase A can phosphorylate residues on β receptors, resulting in inhibition of receptor function. For the β2 receptor, phosphorylation occurs on serine residues both in the third cyto-plasmic loop and in the carboxyl terminal tail of the receptor. Similarly, activation of protein kinase C by Gq-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phospho-rylation by these enzymes.

Adrenoceptor Polymorphisms

Since elucidation of the sequences of the genes encoding the α1, α2, and β subtypes of adrenoceptors, it has become clear that thereare relatively common genetic polymorphisms for many of these receptor subtypes in humans. Some of these may lead to changes in critical amino acid sequences that have pharmacologic impor-tance. Often, distinct polymorphisms occur in specific combina-tions termed haplotypes. Some polymorphisms have been shown to alter susceptibility to diseases such as heart failure, others to alter the propensity of a receptor to desensitize, and still others to alter therapeutic responses to drugs in diseases such as asthma. This remains an area of active research because studies have reported inconsistent results as to the pathophysiologic impor-tance of some polymorphisms.

The Norepinephrine Transporter

When norepinephrine is released into the synaptic cleft, it binds to postsynaptic adrenoceptors to elicit the expected physiologic effect. However, just as the release of neurotransmitters is a tightly regulated process, the mechanisms for removal of neurotransmit-ter must also be highly effective. The norepinephrine transporter (NET) is the principal route by which this occurs. It is particularly efficient in the synapses of the heart, where up to 90% of released norepinephrine is removed by the NET. Remaining synaptic nor-epinephrine may escape into the extrasynaptic space and enter the bloodstream or be taken up into extraneuronal cells and metabo-lized by catecholamine-N-methyltransferase. In other sites such as the vasculature, where synaptic structures are less well developed, removal may still be 60% or more by NET. The NET, often situ-ated on the presynaptic neuronal membrane, pumps the synaptic norepinephrine back into the neuron cell cytoplasm. In the cell, this norepinephrine may reenter the vesicles or undergo metabo-lism through monoamine oxidase to dihydroxyphenylglycol

(DHPG). Elsewhere in the body similar transporters remove dop-amine (dopamine transporter, DAT), serotonin (serotonin trans-porter, SERT), and other neurotransmitters. The NET, surprisingly, has equivalent affinity for dopamine as for norepinephrine, and it can sometimes clear dopamine in brain areas where DAT is low, like the cortex.

Blockade of the NET, eg, by the nonselective psychostimulant cocaine or the NET selective agents atomoxetine or reboxetine, impairs this primary site of norepinephrine removal and thus synaptic norepinephrine levels rise, leading to greater stimulation of α and β adrenoceptors. In the periphery this effect may pro-duce a clinical picture of sympathetic activation, but it is often counterbalanced by concomitant stimulation of α2 adrenoceptors in the brainstem that reduces sympathetic activation.

However, the function of the norepinephrine and dopamine transporters is complex, and drugs can interact with the NET to actually reverse the direction of transport and induce the release of intraneuronal neurotransmitter. This is illustrated in Figure 9–3. Under normal circumstances (panel A), presynaptic NET (red) inactivates and recycles norepinephrine (NE, red) released by vesicular fusion. In panel B, amphetamine (black) acts as both an NET substrate and a reuptake blocker, eliciting reverse transport and blocking normal uptake, thereby increasing NE levels in and beyond the synaptic cleft. In panel C, agents such as methylpheni-date and cocaine (hexagons) block NET-mediated NE reuptake and enhance NE signaling.

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