Physiology 5th Ed.


As noted in the preceding discussion, autonomic receptors are present at the neuromuscular junction, on the cell bodies of postganglionic neurons, and in the effector organs. The type of receptor and its mechanism of action determine the nature of the physiologic response. Furthermore, the physiologic responses are tissue specific and cell type specific.

To illustrate this specificity, compare the effect of activating adrenergic β1 receptors in the SA node to the effect of activating β1 receptors in ventricular muscle. Both the SA node and the ventricular muscle are located in the heart, and their adrenergic receptors and mechanisms of action are the same. The resulting physiologic actions, however, are entirely different. The β1 receptor in the SA node is coupled to mechanisms that increase the spontaneous rate of depolarization and increase heart rate; binding of an agonist such as norepinephrine to this β1 receptor increases the heart rate. The β1 receptor in ventricular muscle is coupled to mechanisms that increase intracellular Ca2+concentration and contractility; binding of an agonist such as norepinephrine to this β1 receptor increases contractility, but it has no direct effect on the heart rate.

The type of receptor also predicts which pharmacologic agonists or antagonists will activate it or block it. The effects of such drugs can be readily predicted by understanding the normal physiologic responses. For example, drugs that are β1 agonists are expected to cause increased heart rate and increased contractility, and drugs that are β1 antagonists are expected to cause decreased heart rate and decreased contractility.

Table 2-4 summarizes the adrenergic and cholinergic receptors, their target tissues, and their mechanisms of action. Table 2-2, its companion, is arranged similarly by receptor type and lists the prototypical drugs that either activate (agonists) or block (antagonists) the receptors. Together, the two tables should be used as a reference for the following discussion about mechanisms of action. These mechanisms involving guanosine triphosphate (GTP)-binding proteins (G proteins), adenylyl cyclase, and inositol 1,4,5-triphosphate (IP3) also are discussed in Chapter 9 in the context of hormone action.

Table 2–4 Location and Mechanism of Action of Autonomic Receptors


Target Tissue

Mechanism of Action



Vascular smooth muscle, skin, renal, and splanchnic

IP3, ↑ intracellular [Ca2+]


Gastrointestinal tract, sphincters


Bladder, sphincter


Radial muscle, iris



Gastrointestinal tract, wall

Presynaptic adrenergic neurons

Inhibition of adenylyl cyclase,

↓ cAMP



Stimulation of adenylyl cyclase,

↑ cAMP


Salivary glands


Adipose tissue





Vascular smooth muscle of skeletal muscle

Stimulation of adenylyl cyclase,

↑ cAMP


Gastrointestinal tract, wall


Bladder, wall






Skeletal muscle, motor end plate (N1)

Opening Na+ and K+ channels → depolarization


Postganglionic neurons, SNS and PNS (N2)

Adrenal medulla (N2)



All effector organs, PNS

Sweat glands, SNS

IP3, ↑ intracellular [Ca2+] (M1, M3, M5)

↓ adenylyl cyclase, ↓ cAMP (M2, M4)

cAMP, Cyclic adenosine monophosphate; PNS, parasympathetic nervous system; SNS, sympathetic nervous system.

G Proteins

Autonomic receptors are coupled to GTP-binding proteins (G proteins) and, therefore, are called G protein–linked receptors. G protein–linked receptors, including those in the autonomic nervous system, are composed of a single polypeptide chain that winds back and forth across the cell membrane seven times; thus, they are also known as seven-pass transmembrane receptor proteins. The ligand (e.g., ACh, norepinephrine) binds to the extracellular domain of its G protein–linked receptor. The intracellular domain of the receptor binds to (is “linked” to) a G protein.

These G proteins are heterotrimeric. In other words, they have three different subunits: α, β, and γ. The α subunit binds either guanosine diphosphate (GDP) or guanosine triphosphate (GTP). When GDP is bound, the α subunit is inactive; when GTP is bound, the α subunit is active. Thus, activity of the G protein resides in its α subunit, and the G protein switches between active and inactive states according to whether it is bound to GDP or GTP. For example, when the G protein releases GDP and binds GTP, it switches from the inactive state to the active state; when GTP is converted back to GDP through intrinsic GTPase activity of the G protein, it switches from the active state to the inactive state.

G proteins couple G protein–linked autonomic receptors to enzymes that execute physiologic actions. These enzymes are adenylyl cyclase and phospholipase C, which, when activated, generate a second messenger (cyclic adenosine monophosphate [cAMP] or IP3, respectively). The second messenger then amplifies the message and executes the final physiologic action. In some cases (e.g., certain muscarinic receptors), the G protein directly alters the function of an ion channel without the mediation of a second messenger.


Adrenoreceptors are found in target tissues of the sympathetic nervous system and are activated by the catecholamines norepinephrine and epinephrine. Norepinephrine is released from postganglionic neurons of the sympathetic nervous system. Epinephrine is secreted by the adrenal medulla and reaches the target tissues via the circulation. Adrenoreceptors are divided into two types, α and β, which are further designated as α1, α2, β1, and β2 receptors. Each of the receptor types has a different mechanism of action (except the β1 and β2 receptors, which have the same mechanism of action), resulting in different physiologic effects (see Tables 2-3 and 2-4).

α1 Receptors

α1 Receptors are found in vascular smooth muscle of the skin, skeletal muscle, and the splanchnic region, in the sphincters of the gastrointestinal tract and bladder, and in the radial muscle of the iris. Activation of α1 receptors leads to contraction in each of these tissues. The mechanism of action involves a G protein called Gq and activation of phospholipase C, illustrated in Figure 2-6. The circled numbers in the figure correspond to the steps discussed as follows:


Figure 2–6 Mechanism of action of α1adrenoreceptors. In the inactive state, the αq subunit of the Gq protein is bound to GDP. In the active state, with norepinephrine bound to the α1 receptor, the αq subunit is bound to GTP. αq, β, and γ are subunits of the Gq protein. The circled numbers correspond to steps discussed in the text. ER, Endoplasmic reticulum; GDP, guanosine diphosphate; Gq, G protein; GTP, guanosine triphosphate; PIP2, phosphatidylinositol 4,5-diphosphate; SR, sarcoplasmic reticulum.

1.     The α1 receptor is embedded in the cell membrane, where it is coupled, via the Gq protein, to phospholipase C. In the inactive state, the αq subunit of the heterotrimeric Gq protein is bound to GDP.

2.     When an agonist such as norepinephrine binds to the α1 receptor (Step 1), a conformational change occurs in the αq subunit of the Gq protein. This conformational change has two effects (Step 2): GDP is released from the αqsubunit and replaced by GTP, and the αq subunit (with GTP attached) detaches from the rest of the Gq protein.

3.     The αq-GTP complex migrates within the cell membrane and binds to and activates phospholipase C (Step 3). Intrinsic GTPase activity then converts GTP back to GDP, and the αq subunit returns to the inactive state (not shown).

4.     Activated phospholipase C catalyzes the liberation of diacylglycerol and IP3 from phosphatidylinositol 4,5-diphosphate (Step 4). The IP3 that is generated causes the release of Ca2+ from intracellular stores in the endoplasmic or sarcoplasmic reticulum, resulting in an increase in intracellular Ca2+ concentration (Step 5). Together, Ca2+ and diacylglycerol activate protein kinase C (Step 6), which phosphorylates proteins. These phosphorylated proteins execute the final physiologic actions (Step 7) such as contraction of smooth muscle.

α2 Receptors

α2 Receptors are inhibitory, are located both presynaptically and postsynaptically, and are less common than α1 receptors. They are found on presynaptic adrenergic and cholinergic nerve terminals and in the gastrointestinal tract. α2receptors are found in two forms, autoreceptors and heteroreceptors.

α2 Receptors present on sympathetic postganglionic nerve terminals are called autoreceptors. In this function, activation of α2 receptors by norepinephrine released from presynaptic nerve terminals inhibits further release of norepinephrine from the same terminals; this negative feedback conserves norepinephrine in states of high stimulation of the sympathetic nervous system. Interestingly, the adrenal medulla does not have α2 receptors and, therefore, is not subject to feedback inhibition; consequently, the adrenal medulla can become depleted of catecholamines during periods of prolonged stress.

α2 Receptors present on parasympathetic postganglionic nerve terminals of the gastrointestinal tract are called heteroreceptors. Norepinephrine is released from sympathetic postganglionic fibers that synapse on these parasympathetic postganglionic fibers. When activated by norepinephrine, the α2 receptors cause inhibition of release of acetylcholine from the parasympathetic postganglionic nerve terminals. In this way, the sympathetic nervous system indirectly inhibits gastrointestinal function (i.e., by inhibiting the parasympathetic activity).

The mechanism of action of these receptors involves the inhibition of adenylyl cyclase, described by the following steps:

1.     The agonist (e.g., norepinephrine) binds to the α2 receptor, which is coupled to adenylyl cyclase by an inhibitory G protein, Gi.

2.     When norepinephrine is bound, the Gi protein releases GDP and binds GTP, and the αi subunit dissociates from the G protein complex.

3.     The αi subunit then migrates in the membrane and binds to and inhibits adenylyl cyclase. As a result, cAMP levels decrease, producing the final physiologic action.

β1 Receptors

β1 Receptors are prominent in the heart. They are present in the SA node, in the atrioventricular (AV) node, and in ventricular muscle. Activation of β1 receptors in these tissues produces increased heart rate in the SA node, increased conduction velocity in the AV node, and increased contractility in ventricular muscle, respectively. β1 Receptors also are located in the salivary glands, in adipose tissue, and in the kidney (where they promote renin secretion). The mechanism of action of β1 receptors involves a Gs protein and activation of adenylyl cyclase. This action is illustrated in Figure 2-7 and involves the following steps, which correspond to the circled numbers in the figure:


Figure 2–7 Mechanism of action of β adrenoreceptors. In the inactive state, the αs subunit of the Gs protein is bound to GDP. In the active state, with norepinephrine bound to the β receptor, the αs subunit is bound to GTP. β1 and β2 receptors have the same mechanism of action. The circled numbers correspond to steps discussed in the text. ATP, Adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GDP, guanosine diphosphate; GTP, guanosine triphosphate.

1.     Similar to other autonomic receptors, β1 receptors are embedded in the cell membrane. They are coupled, via a Gs protein, to adenylyl cyclase. In the inactive state, the αs subunit of the Gs protein is bound to GDP.

2.     When an agonist such as norepinephrine binds to the β1 receptor (Step 1), a conformational change occurs in the αs subunit. This change has two effects (Step 2): GDP is released from the αs subunit and replaced by GTP, and the activated αs subunit detaches from the G protein complex.

3.     The αs-GTP complex migrates within the cell membrane and binds to and activates adenylyl cyclase (Step 3). GTPase activity converts GTP back to GDP, and the αs subunit is returned to its inactive state (not shown).

4.     Activated adenylyl cyclase catalyzes the conversion of ATP to cAMP, which serves as the second messenger (Step 4). cAMP, via steps involving activation of protein kinases, initiates the final physiologic actions (Step 5). As mentioned previously, these physiologic actions are tissue specific and cell type specific. When β1 receptors are activated in the SA node, heart rate increases; when β1 receptors are activated in ventricular muscle, contractility increases; when β1 receptors are activated in the salivary gland, secretion increases; when β1 receptors are activated in the kidney, renin is secreted.

β2 Receptors

β2 Receptors are found in the vascular smooth muscle of skeletal muscle, in the walls of the gastrointestinal tract and bladder, and in the bronchioles. The activation of β2 receptors in these tissues leads to relaxation or dilation. The β2 receptors have a mechanism of action similar to that of β1 receptors: activation of a Gs protein, release of the αs subunit, stimulation of adenylyl cyclase, and generation of cAMP (see Fig. 2-7).

Responses of Adrenoreceptors to Norepinephrine and Epinephrine

There are significant differences in the responses of α1, β1, and β2 adrenoreceptors to the catecholamines epinephrine and norepinephrine. These differences are explained as follows, recalling that norepinephrine is the catecholamine released from postganglionic sympathetic adrenergic nerve fibers, while epinephrine is the primary catecholamine released from the adrenal medulla: (1) Norepinephrine and epinephrine have almost the same potency at α1receptors, with epinephrine being slightly more potent. However, compared with β receptors, α1 receptors are relatively insensitive to catecholamines. Higher concentrations of catecholamines are necessary to activate α1 receptors than to activate β receptors. Physiologically, such high concentrations are reached locally when norepinephrine is released from postganglionic sympathetic nerve fibers but not when catecholamines are released from the adrenal medulla. For example, the amount of epinephrine (and norepinephrine) released from the adrenal medulla in the fight or flight response is insufficient to activate α1 receptors. (2) Norepinephrine and epinephrine are equipotent at β1receptors. As noted previously, much lower concentrations of catecholamines will activate β1 receptors than will activate α1 receptors. Thus, norepinephrine released from sympathetic nerve fibers or epinephrine released from the adrenal medulla will activate β1 receptors. (3) β2 receptorsare preferentially activated by epinephrine. Thus, epinephrine released from the adrenal medulla is expected to activate β2 receptors, whereas norepinephrine released from sympathetic nerve endings is not.


There are two types of cholinoreceptors: nicotinic and muscarinic. Nicotinic receptors are found on the motor end plate, in all autonomic ganglia, and on chromaffin cells of the adrenal medulla. Muscarinic receptors are found in all effector organs of the parasympathetic division and in a few effector organs of the sympathetic division.

Nicotinic Receptors

Nicotinic receptors are found in several important locations: on the motor end plate of skeletal muscle, on all postganglionic neurons of both sympathetic and parasympathetic nervous systems, and on the chromaffin cells of the adrenal medulla. ACh is the natural agonist, which is released from motoneurons and from all preganglionic neurons.

The question arises as to whether the nicotinic receptor on the motor end plate is identical to the nicotinic receptor in the autonomic ganglia. This question can be answered by examining the actions of drugs that serve as agonists or antagonists to the nicotinic receptor. The nicotinic receptors at the two loci are certainly similar: Both are activated by the agonists ACh, nicotine, and carbachol, and both are antagonized by the drug curare (see Table 2-2). However, another antagonist to the nicotinic receptor, hexamethonium, blocks the nicotinic receptor in the ganglia but not the nicotinic receptor on the motor end plate. Thus, it can be concluded that the receptors at the two loci are similar but not identical, where the nicotinic receptor on the skeletal muscle end plate is designated N1 and the nicotinic receptor in the autonomic ganglia is designated N2. This pharmacologic distinction predicts that drugs such as hexamethonium will be ganglionic-blocking agents but not neuromuscular-blocking agents.

A second conclusion can be drawn about ganglionic-blocking agents such as hexamethonium. These agents should inhibit nicotinic receptors in both sympathetic and parasympathetic ganglia, and thus, they should produce widespread effects on autonomic function. However, to predict the actions of ganglionic-blocking agents on a particular organ system, it is necessary to know whether sympathetic or parasympathetic control is dominant in that organ. For example, vascular smooth muscle has only sympathetic innervation, which causes vasoconstriction; thus, ganglionic-blocking agents produce relaxation of vascular smooth muscle and vasodilation. (Because of this property, ganglionic-blocking agents can be used to treat hypertension.) On the other hand, male sexual function is dramatically impaired by ganglionic-blocking agents because the male sexual response has both sympathetic (ejaculation) and parasympathetic (erection) components.

The mechanism of action of nicotinic receptors, whether at the motor end plate or in the ganglia, is based on the fact that this ACh receptor is also an ion channel for Na+ and K+. When the nicotinic receptor is activated by ACh, the channel opens and both Na+ and K+ flow through the channel, down their respective electrochemical gradients.

Figure 2-8 illustrates the function of the nicotinic receptor/channel in two states: closed and open. The nicotinic receptor is an integral cell membrane protein consisting of five subunits: two α, one β, one delta (δ), and one gamma (γ). These five subunits form a funnel around the mouth of a central core. When no ACh is bound, the mouth of the channel is closed. When ACh is bound to each of the two α subunits, a conformational change occurs in all of the subunits, resulting in opening of the central core of the channel. When the core of the channel opens, Na+ and K+ flow down their respective electrochemical gradients (Na+ into the cell, and K+ out of the cell), with each ion attempting to drive the membrane potential to its equilibrium potential. The resulting membrane potential is midway between the Na+ and K+equilibrium potentials, approximately 0 millivolts, which is a depolarized state.


Figure 2–8 Mechanism of action of nicotinic cholinoreceptors. The nicotinic receptor for acetylcholine (ACh) is an ion channel for Na+ and K+. The receptor has five subunits: two α, one β, one δ, and one γ. (Modified from Kandel ER, Schwartz JH: Principles of Neural Science, 4th ed. New York, Elsevier, 2000.)

Muscarinic Receptors

Muscarinic receptors are located in all of the effector organs of the parasympathetic nervous system: in the heart, gastrointestinal tract, bronchioles, bladder, and male sex organs. These receptors also are found in certain effector organs of the sympathetic nervous system, specifically, in sweat glands.

Some muscarinic receptors (e.g., M1, M3, and M5) have the same mechanism of action as the α1 adrenoreceptors (see Fig. 2-6). In these cases, binding of the agonist (ACh) to the muscarinic receptor causes dissociation of the α subunit of the G protein, activation of phospholipase C, and generation of IP3 and diacylglycerol. IP3 releases stored Ca2+, and the increased intracellular Ca2+ with diacylglycerol produces the tissue-specific physiologic actions.

Other muscarinic receptors (e.g., M4) act by inhibiting adenylyl cyclase and decreasing intracellular cAMP levels.

Other muscarinic receptors (M2) alter physiologic processes via a direct action of the G protein. In these cases, no other second messenger is involved. For example, muscarinic receptors in the cardiac SA node, when activated by ACh, produce activation of a Gi protein and release of the αi subunit, which binds directly to K+ channels of the SA node. When the αi subunits bind to K+ channels, the channels open, slowing the rate of depolarization of the SA node and decreasing the heart rate. In this mechanism, there is no stimulation or inhibition of either adenylyl cyclase or phospholipase C and no involvement of any second messenger; rather, the Gi protein acts directly on the ion channel (Box 2-3).

BOX 2–3 Clinical Physiology: Treatment of Motion Sickness with a Muscarinic Receptor Antagonist

DESCRIPTION OF CASE. A woman planning a 10-day cruise asks her physician for medication to prevent motion sickness. The physician prescribes scopolamine, a drug related to atropine, and recommends that she take it for the entire duration of the cruise. While taking the drug, the woman experiences no nausea or vomiting, as hoped. However, she does experience dry mouth, dilation of the pupils (mydriasis), increased heart rate (tachycardia), and difficulty voiding urine.

EXPLANATION OF CASE. Scopolamine, like atropine, blocks cholinergic muscarinic receptors in target tissues. Indeed, it can be used effectively to treat motion sickness, whose etiology involves muscarinic receptors in the vestibular system. The adverse effects that the woman experienced while taking scopolamine can be explained by understanding the physiology of muscarinic receptors in target tissues.

Activation of muscarinic receptors causes increased salivation, constriction of the pupils, decreased heart rate (bradycardia), and contraction of the bladder wall during voiding (see Table 2-2). Therefore, inhibition of the muscarinic receptors with scopolamine would be expected to cause symptoms of decreased salivation (dry mouth), dilation of the pupils (due to the unopposed influence of the sympathetic nervous system on the radial muscles), increased heart rate, and slowed voiding of urine (caused by the loss of contractile tone of the bladder wall).

TREATMENT. Scopolamine is discontinued.