Medical Physiology, 3rd Edition

Synaptic Physiology of the Autonomic Nervous System

The sympathetic and parasympathetic divisions have opposite effects on most visceral targets

All innervation of skeletal muscle in humans is excitatory. In contrast, many visceral targets receive both inhibitory and excitatory synaptic inputs. These antagonistic inputs arise from the two opposing divisions of the ANS, the sympathetic and the parasympathetic.

In organs that are stimulated during physical activity, the sympathetic division is excitatory and the parasympathetic division is inhibitory. For example, sympathetic input increases the heart rate, whereas parasympathetic input decreases it. In organs whose activity increases while the body is at rest, the opposite is true. For example, the parasympathetic division stimulates peristalsis of the gut, whereas the sympathetic division inhibits it.

Although antagonistic effects of the sympathetic and parasympathetic divisions of the ANS are the general rule for most end organs, exceptions exist. For example, the salivary glands are stimulated by both divisions, although stimulation by the sympathetic division has effects different from those of parasympathetic stimulation (see p. 894). In addition, some organs receive innervation from only one of these two divisions of the ANS. For example, sweat glands, piloerector muscles, and most peripheral blood vessels receive input from only the sympathetic division.

Synapses of the ANS are specialized for their function. Rather than possessing synaptic terminals that are typical of somatic motor axons, many postganglionic autonomic neurons have bulbous expansions, or varicosities, that are distributed along their axons within their target organ (Fig. 14-7). It was once believed that these varicosities indicated that neurotransmitter release sites of the ANS did not form close contact with end organs and that neurotransmitters needed to diffuse long distances across the extracellular space to reach their targets. However, we now recognize that many varicosities form synapses with their targets, with a synaptic cleft extending ~50 nm across. At each varicosity, autonomic axons form an “en passant” synapse with their end-organ target. This arrangement results in an increase in the number of targets that a single axonal branch can influence, with wider distribution of autonomic output.

image

FIGURE 14-7 Synapses of autonomic neurons with their target organs. Many axons of postganglionic neurons make multiple points of contact (varicosities) with their targets. In this scanning electron micrograph of the axon of a guinea pig postganglionic sympathetic neuron grown in tissue culture, the arrows indicate varicosities, or en passant synapses. (From Burnstock G: Autonomic neuromuscular junctions: Current developments and future directions. J Anat 146:1–30, 1986.)

All preganglionic neurons—both sympathetic and parasympathetic—release acetylcholine and stimulate N2 nicotinic receptors on postganglionic neurons

At synapses between postganglionic neurons and target cells, the two major divisions of the ANS use different neurotransmitters and receptors (Table 14-1). However, in both the sympathetic and parasympathetic divisions, synaptic transmission between preganglionic and postganglionic neurons (termed ganglionic transmission because the synapse is located in a ganglion) is mediated by acetylcholine (ACh) acting on nicotinic receptors (Fig. 14-8). Nicotinic receptors are ligand-gated channels (i.e., ionotropic receptors) with a pentameric structure (see pp. 212–213). Table 14-2 summarizes some of the properties of nicotinic receptors. The nicotinic receptors on postganglionic autonomic neurons are of a molecular subtype (N2) different from that found at the neuromuscular junction (N1). Both are ligand-gated ion channels activated by ACh or nicotine. However, whereas the N1 receptors at the neuromuscular junction (see p. 212) are stimulated by decamethonium and preferentially blocked by d-tubocurarine, imageN8-2 the autonomic N2 receptors are stimulated by tetramethylammonium but resistant to d-tubocurarine. When activated, N1 and N2 receptors are both permeable to Na+ and K+. Thus, nicotinic transmission triggered by stimulation of preganglionic neurons leads to rapid depolarization of postganglionic neurons.

TABLE 14-1

Properties of the Sympathetic and Parasympathetic Divisions

 

SYMPATHETIC PREGANGLIONIC

SYMPATHETIC POSTGANGLIONIC

PARASYMPATHETIC PREGANGLIONIC

PARASYMPATHETIC POSTGANGLIONIC

Location of neuron cell bodies

Intermediolateral cell column in the spinal cord (T1–L3)

Prevertebral and paravertebral ganglia

Brainstem and sacral spinal cord (S2–S4)

Terminal ganglia in or near target organ

Myelination

Yes

No

Yes

No

Primary neurotransmitter

ACh

Norepinephrine

ACh

ACh

Primary postsynaptic receptor

Nicotinic

Adrenergic

Nicotinic

Muscarinic

image

FIGURE 14-8 Major neurotransmitters of the ANS. In the case of the somatic neuron, the pathway between the CNS and effector cell is monosynaptic. The neuron releases ACh, which binds to N1-type nicotinic receptors on the postsynaptic membrane (i.e., skeletal muscle cell). In the case of both the parasympathetic and sympathetic divisions, the preganglionic neuron releases ACh, which acts at N2-type nicotinic receptors on the postsynaptic membrane of the postganglionic neuron. In the case of the postganglionic parasympathetic neuron, the neurotransmitter is ACh, but the postsynaptic receptor is a muscarinic receptor (i.e., GPCR) of one of five subtypes (M1 to M5). In the case of most postganglionic sympathetic neurons, the neurotransmitter is norepinephrine. The postsynaptic receptor is an adrenergic receptor (i.e., GPCR) of one of two major subtypes (α and β).

TABLE 14-2

Signaling Pathways for Nicotinic, Muscarinic, Adrenergic, and Dopaminergic Receptors

RECEPTOR TYPE

AGONISTS*

ANTAGONISTS

G PROTEIN

LINKED ENZYME

SECOND MESSENGER

N1 nicotinic ACh

ACh (nicotine, decamethonium)

d-Tubocurarine, α-bungarotoxin

N2 nicotinic ACh

ACh (nicotine, TMA)

Hexamethonium

M1/M3/M5 muscarinic ACh

ACh (muscarine)

Atropine, pirenzepine (M1)

q

PLC

IP3 and DAG

M2/M4 muscarinic ACh

ACh (muscarine)

Atropine, methoctramine (M2)

i and Gαo

Adenylyl cyclase

↓ [cAMP]i

α1 adrenergic

NE ≥ Epi (phenylephrine)

Phentolamine

q

PLC

IP3 and DAG

α2 adrenergic

NE ≥ Epi (clonidine)

Yohimbine

i

Adenylyl cyclase

↓ [cAMP]i

β1 adrenergic

Epi > NE (dobutamine, isoproterenol)

Metoprolol

s

Adenylyl cyclase

↑ [cAMP]i

β2 adrenergic

Epi > NE (terbutaline, isoproterenol)

Butoxamine

s

Adenylyl cyclase

↑ [cAMP]i

β3 adrenergic

Epi > NE (isoproterenol)

SR59230A

s

Adenylyl cyclase

↑ [cAMP]i

D1

Dopamine (fenoldopam)

LE 300

s

Adenylyl cyclase

↑ [cAMP]i

D2

Dopamine (quinpirole)

Thioridazine

i

Adenylyl cyclase

↓ [cAMP]i

*Selective agonists are in parentheses.

DAG, diacylglycerol; Epi, epinephrine; NE, norepinephrine; PLC, phospholipase C; TMA, tetramethylammonium.

All postganglionic parasympathetic neurons release ACh and stimulate muscarinic receptors on visceral targets

All postganglionic parasympathetic neurons act through muscarinic ACh receptors on the postsynaptic target (see Fig. 14-8). Activation of this receptor can either stimulate or inhibit function of the target cell. Cellular responses induced by muscarinic receptor stimulation are more varied than are those induced by nicotinic receptors. Muscarinic receptors are G protein–coupled receptors (GPCRs; see pp. 51–66)—also known as metabotropic receptors—that (1) stimulate the hydrolysis of phosphoinositide and thus increase [Ca2+]i and activate protein kinase C, (2) inhibit adenylyl cyclase and thus decrease cAMP levels, or (3) directly modulate K+ channels through the G-protein βγ complex (see pp. 197–198 and 542). Because they are mediated by second messengers, muscarinic responses, unlike the rapid responses evoked by nicotine receptors, are slow and prolonged.

Muscarinic receptors exist in five different pharmacological subtypes (M1 to M5) that are encoded by five different genes. All five subtypes are highly homologous to each other but very different from the nicotinic receptors, which are ligand-gated ion channels. Subtypes M1 through M5 are each stimulated by ACh and muscarine and are blocked by atropine. These muscarinic subtypes have a heterogeneous distribution among tissues, and in many cases a given cell may express more than one subtype. imageN14-3 Although a wide variety of antagonists inhibit the muscarinic receptors, none is completely selective for a specific subtype. However, it is possible to classify a receptor on the basis of its affinity profile for a battery of antagonists. Selective agonists for the different isoforms have not been available.

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Muscarinic Receptors

Contributed by George Richerson

Muscarinic receptors are found both presynaptically and postsynaptically throughout the ANS. Many smooth muscles coexpress multiple muscarinic subtypes, each of which may play a different role in neurotransmission. Thus, it is sometimes difficult to predict the effects of applying ACh to a particular tissue.

A molecular characteristic of the muscarinic receptors is that the third cytoplasmic loop (i.e., between the fifth and sixth membrane-spanning segments) is different in M1, M3, and M5 on the one hand and M2and M4 on the other. This loop appears to play a role in coupling of the receptor to the G protein downstream in the signal-transduction cascade. In general M1, M3, and M5 preferentially couple to Gαq and then to phospholipase C, with release of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (see p. 58). On the other hand M2 and M4 preferentially couple to Gαi or Gαo to inhibit adenylyl cyclase and thus decrease [cAMP]i (see p. 53).

Most postganglionic sympathetic neurons release norepinephrine onto visceral targets

Most postganglionic sympathetic neurons release norepinephrine (see Fig. 14-8), which acts on target cells through adrenergic receptors. The sympathetic innervation of sweat glands is an exception to this rule. imageN14-4 Sweat glands are innervated by sympathetic neurons that release ACh and act via muscarinic receptors (see p. 571). The adrenergic receptors are all GPCRs and are highly homologous to the muscarinic receptors (see p. 341). Two major types of adrenergic receptors are recognized, α and β, each of which exists in multiple subtypes (e.g., α1, α2, β1, β2, and β3). In addition, there are heterogeneous α1 and α2 receptors, with three cloned subtypes of each. Table 14-2 lists the signaling pathways that are generally linked to these receptors. For example, β1 receptors in the heart activate the Gs heterotrimeric G protein and stimulate adenylyl cyclase, which antagonizes the effects of muscarinic receptors.

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Cholinergic Sympathetic Neurons

Contributed by Emile Boulpaep, Walter Boron

From a macroscopic anatomical point of view, there is no doubt that the cholinergic sympathetic nerve endings of sudomotor nerves (i.e., the nerves that cause sweat secretion) and some vasomotor nerves are distal to the sympathetic ganglia. In this sense, these fibers are clearly “postganglionic.” Indeed, these rare cholinergic sympathetic fibers run together from the sympathetic ganglion to the target organ together with the majority of adrenergic fibers.

From a physiological point of view, all of the sympathetic neurons that reach the adrenal medulla (see p. 343) are “preganglionic.” That is, these fibers derive from neuron cell bodies that lie in the intermediolateral cell column of the spinal cord. Their axons then transit through the paravertebral ganglia of the sympathetic trunk (see the left side of Fig. 14-4) without synapsing, and then follow along the splanchnic nerves. Most of these axons then go directly to the adrenal medulla, where they synapse on their targets, the chromaffin cells. However, some axons transit through the celiac ganglion—again without synapsing—before reaching their target chromaffin cells in the adrenal medulla. Thus, all sympathetic fibers that synapse on chromaffin cells are physiologically “preganglionic”: a single neuron carries information from the spinal cord to the target cell. However, the sympathetic neurons that traverse the celiac ganglion before reaching the adrenal medulla could—from a macroscopic anatomical point of view—be regarded as postganglionic.

Authors in the 1960s and 1970s suggested that cholinergic sympathetic fibers that innervate the sweat glands (see pp. 342 and 571) and some of the vascular smooth muscle in skeletal muscle (see p. 539) derive from neuronal cell bodies in the spinal cord. This situation would be analogous to that of the cholinergic sympathetic innervation of the adrenal medulla. If this were true, then one could regard these cholinergic sympathetic sudomotor/vasomotor fibers—physiologically—as being “preganglionic.” However, more recent experiments suggest that these cholinergic sympathetic fibers can arise from neuron cell bodies located in sympathetic ganglia and that these neurons develop from neural crest cells (see p. 261). Using antibodies directed against choline acetyltransferase (i.e., the enzyme that catalyzes the conversion of acetyl coenzyme A and choline into ACh; see Fig. 13-8B and p. 210) and the vesicular ACh transporter (VAChT, which transports ACh from the cytoplasm of the nerve terminal into the synaptic vesicles; see Fig. 8-15), Schäfer and colleagues demonstrated that VAChT-positive “principal ganglionic cells” (i.e., postganglionic neurons) are present in paravertebral sympathetic ganglia at all levels of the thoracolumbar paravertebral chain. These observations are consistent with the idea that sudomotor nerve fibers and some vasomotor nerve fibers (e.g., skeletal microvasculature) are cholinergic postganglionic sympathetic neurons. These authors also demonstrated VAChT-positive principal ganglionic cells in two other sympathetic ganglia: the stellate and superior cervical ganglia.

Schäfer and colleagues also studied the developmental biology of postganglionic sympathetic neurons. They found that a small minority of sympathetic neurons have a cholinergic phenotype even during early embryonic development—before the neurons innervate sweat glands.

Thus, a true postganglionic sympathetic neuron—postganglionic in both the gross anatomical and the physiological sense of the word—can be cholinergic. In other words, a preganglionic sympathetic “first” neuron, with its cell body in the intermediolateral column, may synapse in a sympathetic ganglion with a postganglionic sympathetic “second” neuron that releases ACh at its nerve terminals. Thus, it is no longer necessary to assume that cholinergic sympathetic sudomotor/vasomotor neurons are, in fact, preganglionic fibers that traversed the sympathetic ganglion without synapsing.

References

Schäfer MK, Eiden LE, Weihe E. Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine receptor. II. The peripheral nervous system. Neuroscience. 1998;84:361–376.

Schäfer MK, Schutz B, Weihe E, Eiden LE. Target-independent cholinergic differentiation in the rat sympathetic nervous system. Proc Natl Acad Sci U S A. 1997;94:4149–4154.

Adrenergic receptor subtypes have a tissue-specific distribution. α1 receptors predominate on blood vessels, α2 on presynaptic terminals, β1 in the heart, β2 in high concentration in the bronchial muscle of the lungs, and β3 in fat cells. This distribution has permitted the development of many clinically useful agents that are selective for different subtypes and tissues. For example, α1 agonists are effective as nasal decongestants, and α2 antagonists have been used to treat impotence. β1 agonists increase cardiac output in congestive heart failure, whereas β1 antagonists are useful antihypertensive agents. β2 agonists are used as bronchodilators in patients with asthma and chronic lung disease.

The adrenal medulla (see pp. 1030–1034) is a special adaptation of the sympathetic division, homologous to a postganglionic sympathetic neuron (see Fig. 14-8). It is innervated by preganglionic sympathetic neurons, and the postsynaptic target cells, which are called chromaffin cells, have nicotinic ACh receptors. However, rather than possessing axons that release norepinephrine onto a specific target organ, the chromaffin cells reside near blood vessels and release epinephrine into the bloodstream. This neuroendocrine component of sympathetic output enhances the ability of the sympathetic division to broadcast its output throughout the body. Norepinephrine and epinephrine both activate all five subtypes of adrenergic receptor, but with different affinities (see Table 14-2). In general, the α receptors have a greater affinity for norepinephrine, whereas the β receptors have a greater affinity for epinephrine.

Postganglionic sympathetic and parasympathetic neurons often have muscarinic as well as nicotinic receptors

The simplified scheme described in the preceding discussion is very useful for understanding the function of the ANS. However, two additional layers of complexity are superimposed on this scheme. First, some postganglionic neurons, both sympathetic and parasympathetic, have muscarinic in addition to nicotinic receptors. Second, at all levels of the ANS, certain neurotransmitters and postsynaptic receptors are neither cholinergic nor adrenergic. We discuss the first exception in this section and the second in the following section.

If we stimulate the release of ACh from preganglionic neurons or apply ACh to an autonomic ganglion, many postganglionic neurons exhibit both nicotinic and muscarinic responses. Because nicotinic receptors (N2) are ligand-gated ion channels, nicotinic neurotransmission causes a fast, monophasic excitatory postsynaptic potential (EPSP). In contrast, because muscarinic receptors are GPCRs, neurotransmission by this route leads to a slower electrical response that can be either inhibitory or excitatory. Thus, depending on the ganglion, the result is a multiphasic postsynaptic response that can be a combination of a fast EPSP through a nicotinic receptor plus either a slow EPSP or a slow inhibitory postsynaptic potential (IPSP) through a muscarinic receptor. Figure 14-9A shows a fast EPSP followed by a slow EPSP.

image

FIGURE 14-9 An example of dual nicotinic and muscarinic neurotransmission between sympathetic preganglionic and postganglionic neurons. A, Stimulation of a frog preganglionic sympathetic neuron releases ACh, which triggers a fast EPSP (due to activation of nicotinic receptors on the postganglionic sympathetic neuron), followed by a slow EPSP (due to activation of muscarinic receptors on the postganglionic neuron). B, In a rat sympathetic postganglionic neuron, the M current (mediated by a K+ channel) is normally active, hyperpolarizing the neuron. Thus, injecting current elicits only a single action potential. C, In the same experiment as in B, adding muscarine stimulates a muscarinic receptor (i.e., GPCR) and triggers a signal-transduction cascade that blocks the M current. One result is a steady-state depolarization of the cell. Injecting current now elicits a train of action potentials. (A, Data from Adams PR, Brown DA: Synaptic inhibition of the M-current: Slow excitatory post-synaptic potential mechanism in bullfrog sympathetic neurones. J Physiol 332:263–272, 1982; B and C,data from Brown DA, Constanti A: Intracellular observations on the effects of muscarinic agonists on rat sympathetic neurones. Br J Pharmacol 70:593–608, 1980.)

A well-characterized effect of muscarinic neurotransmission in autonomic ganglia is inhibition of a specific K+ current called the M current. The M current is widely distributed in visceral end organs, autonomic ganglia, and the CNS. In the baseline state, the K+ channel that underlies the M current is active and thereby produces slight hyperpolarization. In the example shown in Figure 14-9B, with the stabilizing M current present, electrical stimulation of the neuron causes only a single spike. If we now add muscarine to the neuron, activation of the muscarinic receptor turns off the hyperpolarizing M current and thus leads to a small depolarization. If we repeat the electrical stimulation in the continued presence of muscarine (see Fig. 14-9C), repetitive spikes appear because loss of the stabilizing influence of the M current increases the excitability of the neuron. The slow, modulatory effects of muscarinic responses greatly enhance the ability of the ANS to control visceral activity beyond what could be accomplished with only fast nicotinic EPSPs.

Nonclassic transmitters can be released at each level of the ANS

In the 1930s, Sir Henry Dale imageN14-5 first proposed that sympathetic nerves release a transmitter similar to epinephrine (now known to be norepinephrine) and parasympathetic nerves release ACh. For many years, attention was focused on these two neurotransmitters, primarily because they mediate large and fast postsynaptic responses that can be easily studied. In addition, a variety of antagonists are available to block cholinergic and adrenergic receptors and thereby permit clear characterization of the roles of these receptors in the control of visceral function. More recently, it has become evident that some neurotransmission in the ANS involves neither adrenergic nor cholinergic pathways. Moreover, many neuronal synapses use more than a single neurotransmitter. Such cotransmission is now known to be common in the ANS. As many as eight different neurotransmitters may be found within some neurons, a phenomenon known as colocalization (see Table 13-1). Thus, ACh and norepinephrine play important but not exclusive roles in autonomic control.

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Sir Henry H. Dale

For more information about Sir Henry H. Dale and the work that led to his Nobel Prize, visit http://www.nobel.se/medicine/laureates/1936/index.html (accessed October 2014).

The distribution and function of nonadrenergic, noncholinergic (NANC) transmitters are only partially understood. However, these transmitters are found at every level of autonomic control (Table 14-3), where they can cause a wide range of postsynaptic responses. These nonclassic transmitters may cause slow synaptic potentials or may modulate the response to other inputs (as in the case of the M current) without having obvious direct effects. In other cases, nonclassic transmitters have no known effects and may be acting in ways that have not yet been determined.

TABLE 14-3

Neurotransmitters Present Within the ANS

 

CNS NEURONS

PREGANGLIONIC AUTONOMIC NEURONS

POSTGANGLIONIC AUTONOMIC NEURONS

VISCERAL AFFERENT NEURONS

GANGLION INTERNEURONS

ENTERIC NEURONS

ACh

 

X

X

     

Monoamines

           

Norepinephrine

X

 

X

   

X

Epinephrine

           

5-hydroxytryptamine

X

       

X

Dopamine

       

X

X

Amino acids

           

Glutamate

X

         

Glycine

X

         

Gamma-aminobutyric acid

         

X

Neuropeptides

           

Substance P

X

X

 

X

 

X

Thyrotropin-releasing hormone

X

         

Enkephalins

X

     

X

X

Neuropeptide Y

X

 

X

   

X

Neurotensin

X

       

X

Neurophysin II

X

         

Oxytocin

X

         

Somatostatin

X

 

X

   

X

Calcitonin gene–related peptide

 

X

 

X

 

X

Galanin

   

X

   

X

Vasoactive intestinal peptide

   

X

   

X

Endogenous opioids

   

X

   

X

Tachykinins (substance P, neurokinin A, neuropeptide K, neuropeptide γ)

         

X

Cholecystokinin

         

X

Gastrin-releasing peptide

         

X

Nonclassical

           

NO

   

X

   

X

ATP

   

X

   

X

Although colocalization of neurotransmitters is recognized as a common property of neurons, it is not clear what controls the release of each of the many neurotransmitters. In some cases, the proportion of neurotransmitters released depends on the level of neuronal activity (see pp. 327–328). For example, medullary raphé neurons project to the intermediolateral cell column in the spinal cord, where they co-release serotonin, thyrotropin-releasing hormone, and substance P onto sympathetic preganglionic neurons. The proportions of released neurotransmitters are controlled by neuronal firing frequency: at low firing rates, serotonin is released alone; at intermediate firing rates, thyrotropin-releasing hormone is also released; and at high firing rates, all three neurotransmitters are released. This frequency-dependent modulation of synaptic transmission provides a mechanism for enhancing the versatility of the ANS.

Two of the most unusual nonclassic neurotransmitters, ATP and nitric oxide, were first identified in the ANS

It was not until the 1970s that a nonadrenergic, noncholinergic class of sympathetic or parasympathetic neurons was first proposed by Geoffrey Burnstock and colleagues, who suggested that ATP might act as the neurotransmitter. This idea, that a molecule used as an intracellular energy substrate could also be a synaptic transmitter, was initially difficult to prove. However, it is now clear that neurons use a variety of classes of molecules for intercellular communication (see pp. 314–322). Two of the most surprising examples of nonclassic transmitters, nitric oxide (NO) and ATP, were first identified and studied as neurotransmitters in the ANS, but they are now known to be more widely used throughout the nervous system.

ATP

ATP is colocalized with norepinephrine in postganglionic sympathetic vasoconstrictor neurons. It is contained in synaptic vesicles, is released on electrical stimulation, and induces vascular constriction when it is applied directly to vascular smooth muscle. The effect of ATP results from activation of P2 purinoceptors on smooth muscle, which include ligand-gated ion channels (P2X) and GPCRs (P2Y and P2U). P2X receptors are present on autonomic neurons and smooth-muscle cells of blood vessels, the urinary bladder, and other visceral targets. P2X receptor channels have a relatively high Ca2+ permeability (see p. 327). In smooth muscle, ATP-induced depolarization can also activate voltage-gated Ca2+ channels (see pp. 189–190) and thus lead to an elevation in [Ca2+]i and a rapid phase of contraction (Fig. 14-10). Norepinephrine, by binding to α1 adrenergic receptors, acts through a heterotrimeric G protein (see pp. 51–66) to facilitate the release of Ca2+ from intracellular stores and thereby produce a slower phase of contraction. Finally, the release of neuropeptide Y may, after prolonged and intense stimulation, elicit a third component of contraction.

image

FIGURE 14-10 Cotransmission with ATP, norepinephrine, and neuropeptide Y in the ANS. In this example, stimulation of a postganglionic sympathetic neuron causes three phases of contraction of a vascular smooth-muscle cell. Each phase corresponds to the response of the postsynaptic cell to a different neurotransmitter or group of transmitters. In phase 1, ATP binds to a P2X purinoceptor (a ligand-gated cation channel) on the smooth-muscle cell, which leads to depolarization, activation of voltage-gated Ca2+ channels, increased [Ca2+]i, and the rapid phase of contraction. In phase 2, norepinephrine, acting through an α1 adrenergic receptor and a Gq/PLC/IP3 cascade, leads to Ca2+ release from internal stores and the second phase of contraction. In phase 3, when neuropeptide Y is present, it acts through a Y1 receptor to somehow cause an increase in [Ca2+]i and thus produces the slowest phase of contraction. ER, endoplasmic reticulum; PLC, phospholipase C.

Nitric Oxide

In the 1970s, it was also discovered that the vascular endothelium produces a substance that induces relaxation of vascular smooth muscle. First called endothelium-derived relaxation factor, it was identified as the free radical NO in 1987. NO is an unusual molecule for intercellular communication because it is a short-lived gas. It is produced locally from L-arginine by the enzyme nitric oxide synthase (NOS; see pp. 66–67). The NO then diffuses a short distance to a neighboring cell, where its effects are primarily mediated by the activation of guanylyl cyclase.

NOS is found in the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic divisions as well as in vascular endothelial cells. It is not specific for any type of neuron inasmuch as it is found in both norepinephrine- and ACh-containing cells as well as neurons containing a variety of neuropeptides. Figure 14-11 shows how a parasympathetic neuron may simultaneously release NO, ACh, and vasoactive intestinal peptide, each acting in concert to lower [Ca2+]i and relax vascular smooth muscle.

image

FIGURE 14-11 Action of NO in the ANS. Stimulation of a postganglionic parasympathetic neuron can cause more than one phase of relaxation of a vascular smooth-muscle cell, corresponding to the release of a different neurotransmitter or group of transmitters. The first phase in this example is mediated by both NO and ACh. The neuron releases NO, which diffuses to the smooth-muscle cell. In addition, ACh binds to M3 muscarinic receptors (i.e., GPCRs) on endothelial cells; this leads to production of NO, which also diffuses to the smooth-muscle cell. Both sources of NO activate guanylyl cyclase (GC) and raise [cGMP]i in the smooth muscle cell and contribute to the first phase of relaxation. In the second phase, which tends to occur more with prolonged or intense stimulation, the neuropeptide VIP (or a related peptide) binds to receptors on the smooth-muscle cell and causes delayed relaxation through an increase in [cAMP]i or a decrease in [Ca2+]i.