CHAPTER 2

Autonomic Nervous System

The motor (efferent) nervous system has two compo-
nents: the somatic and the autonomic. These two organization and General Features of t he
systems differ in a number of ways but are chiefly Autonomic Nervous system, 47
distinguished by the types of effector organs they Autonomic Receptors, 59
innervate and the types of functions they control.
The somatic nervous system is a voluntary motor summary, 66
system under conscious control. Each of its pathways Challenge Yourself, 66
consists of a single motoneuron and the skeletal muscle
fibers it innervates. The cell body of the motoneuron
is located in the central nervous system, in either the brain stem or spinal cord, and its
axon synapses directly on skeletal muscle, the effector organ. The neurotransmitter
acetylcholine is released from presynaptic terminals of the motoneurons and activates
nicotinic receptors located on the motor end plates of the skeletal muscle. An action
potential in the motoneuron causes an action potential in the muscle fiber, which causes
the muscle to contract. (For a complete discussion of the somatic nervous system, see
Chapter 1.)
The autonomic nervous system is an involuntary system that controls and modulates
the functions primarily of visceral organs. Each pathway in the autonomic nervous
system consists of two neurons: a preganglionic neuron and a postganglionic neuron.
The cell body of each preganglionic neuron resides in the central nervous system. The
axons of these preganglionic neurons synapse on the cell bodies of postganglionic
neurons in one of several autonomic ganglia located outside the central nervous system.
The axons of the postganglionic neurons then travel to the periphery, where they synapse
on visceral effector organs such as the heart, bronchioles, vascular smooth muscle,
gastrointestinal tract, bladder, and genitalia. All preganglionic neurons of the autonomic
nervous system release acetylcholine. Postganglionic neurons release either acetylcholine
or norepinephrine or, in some cases, neuropeptides.

ORGANIZATION AND GENERAL FEATURES OF THE

AUTONOMIC NERVOUS SYSTEM
The autonomic nervous system has two major divisions: the sympathetic and the
parasympathetic, which often complement each other in the regulation of organ system
function. A third division of the autonomic nervous system, the enteric nervous system,
is located in plexuses of the gastrointestinal tract. (The enteric nervous system is dis-
cussed in Chapter 8.)
The organization of the autonomic nervous system is described in Figure 2.1 and its
companion, Table 2.1. The sympathetic and parasympathetic divisions are included and,
for comparison, so is the somatic nervous system.
47
48 • Physiology

CENTRAL NERVOUS SYSTEM EFFECTOR ORGANS

Somat ic
Motoneuron
- - - - - - - - - - - - - - - - - - - - - - - - - < ACh
Q
'V Skeletal muscle

Sympathetic
•
Preganglionic Postganglionic
( ACh 1 3 t - - - - - - - - - - - - - - < (NE
u
2
Smooth muscle,
glands

ACh ~ SWeat glaod•'

Preganglionic Postganglionic {)
Parasympathetic - - - - - - - - - - - - - - - - - < ACh !Edt ( ACh M Smooth muscle,
glands

Preganglionic ~ __To_ c_1·r_c_u1_af_1o_n_ • Epinephrine {80%)

Adrenal medulla ••......- - - - - - < (ACh N2
Norepinephrine {20%)
Adrenal medulla

Fig. 2.1 Organization of the autonomic nervous system. The somatic nervous system is
included for comparison. ACh, Acetvlcholine; M, muscarinic receptor; N, nicotinic receptor; NE,
norepinephrine. *SWeat glands have sympathetic cholinergic innervation.

postganglionic parasympathetic neurons of the gastro-

Terminology
intestinal tract that release peptides [e.g., substance Pl
The terms sympathetic and parasympathetic are strictly or other substances [e.g., nitric oxide (NO) ] as their
anatomic terms and refer to the anatomic origin of the neurotransmitter rather than ACh.)
preganglionic neurons in the central nervous system To summarize, whether located in the sympathetic
(CNS; see Table 2.1). Preganglionic neurons in the division or in the parasympathetic division, all pregan-
sympathetic division originate in the thoracolumbar glionic neurons release ACh and therefore are called
spinal cord. Preganglionic neurons in the parasympa- cholinergic. Postganglionic neurons may be either
thetic division originate in the brain stem and sacral adrenergic (they release norepinephrine) or cholinergic
spinal cord. (they release ACh). Most postganglionic parasympa-
The terms adrenergic and cholinergic are used thetic neurons are cholinergic; postganglionic sympa-
to describe neurons of either division, according to thetic neurons may be either adrenergic or cholinergic.
which neurotransmitter they synthesize and release.
Adrenergic neurons release norepinephrine; receptors
Neuroettector Junctions of the Autonomic
for norepinephrine on the effector organs are called
Nervous system
adrenoreceptors. Adrenoreceptors may be activated
by norepinephrine, which is released from adrenergic The junctions between postganglionic autonomic
neurons, or by epinephrine, which is secreted into neurons and their effectors (target tissues), the neuro-
the circulation by the adrenal medulla. Cholinergic effector junctions, are analogous to the neuromuscular
neurons release acetylcholine (ACh); receptors for junctions of the somatic nervous system. There
ACh are called cholinoreceptors. (A third term is are, however, several structural and functional differ-
nonadrenergic, noncholinergic, which describes some ences with the neuromuscular junction. (1) The
 2- Autonomic Ne1110us System • 49

TABLE 2.1 organization of the Autonomic Nervous system

Somatic Nervous
Characteristics Sympathetic Division Parasympathetic Division System•
Origin of preganglionic Spinal cord segments Nuclei of CN III, VII, IX, and
neurons Tl-L3 X; spinal cord segments
(thoracolumbar) S2- S4 (craniosacral)
Location of autonomic ganglia Paravertebral and In or near effector organs
prevertebral
Length of preganglionic axons Short Long
Length of postganglionic Long Short
axons
Effector organs Smooth muscle; cardiac Smooth muscle; cardiac Skeletal muscle
muscle; glands muscle; glands
Neuroeffector junctions Diffuse, branching; Diffuse, branching; receptors Discrete, organized;
receptors not not concentrated in one ACh receptors
concentrated in one region localized on motor
region end plate
Neurotransmitter and receptor ACh/ nicotinic receptor ACh/ nicotinic receptor
type in ganglion
Neurotransmitter in effector Norepinephrine (except ACh Ach
organs sweat glands)
Receptor types in effector ai, a2, P1, P2 Muscarinic Nicotinic
organs

•somatic nervous system is included for comparison.

ACh, Acetylcholine; CN, cranial nerve.

neuromuscular junction (discussed in Chapter 1) has a and alertness. Although this response, per se, is rarely
discrete arrangement, whereby the "effector," a skeletal employed, the sympathetic nervous system operates
muscle fiber, is innervated by a single motoneuron. In continuously to modulate the functions of many organ
contrast, in the autonomic nervous system, the post- systems such as heart, blood vessels, gastrointestinal
ganglionic neurons that innervate target tissues form tract, bronchi, and sweat glands.
diffuse, branching networks. Beads, or varicosities, Figure 2.2 depicts the organization of the sympa-
line these branches and are the sites of neurotransmitter thetic nervous system in relation to the spinal cord, the
synthesis, storage, and release. The varicosities are sympathetic ganglia, and the effector organs in the
therefore analogous to the presynaptic nerve terminals periphery. The preganglionic sympathetic neurons
of the neuromuscular junction. (2) There is overlap in originate in nuclei of the thoracolumbar spinal cord,
the branching networks from different postganglionic leave the spinal cord via the ventral motor roots and
neurons, such that target tissues may be innervated by white rami, and project either to the paravertebral
many postganglionic neurons. (3) In the autonomic ganglia of the sympathetic chain or to a series of pre-
nervous system, postsynaptic receptors are widely vertebral ganglia. Thus one category of preganglionic
distributed on the target tissues, and there is no special- neuron synapses on postganglionic neurons in paraver-
ized region of receptors analogous to the motor end tebral ganglia (e.g., superior cervical ganglion) of the
plate of skeletal muscle. sympathetic chain. These synapses may occur in
ganglia at the same segmental level of the chain, or the
preganglionic fibers may turn in the cranial or caudal
sympathetic Nervous system
direction and innervate ganglia at higher or lower levels
The overall function of the sympathetic nervous system in the chain, thereby permitting synapses in multiple
is to mobilize the body for activity. In the extreme, ganglia (consistent with the diffuseness of sympathetic
if a person is exposed to a stressful situation, the sym- functions) . The other category of preganglionic neuron
pathetic nervous system is activated with a response passes through the sympathetic chain without synaps-
known as "fight or flight," which includes increased ing and continues on to synapse in prevertebral ganglia
arterial pressure, increased blood flow to active (celiac, superior mesenteric, and inferior mesenteric)
muscles, increased metabolic rate, increased blood that supply visceral organs, glands, and the enteric
glucose concentration, and increased mental activity nervous system of the gastrointestinal tract. In the
50 • Physiology

SYMPATHETIC NERVOUS SYSTEM

Lacrimal gland

Radial muscle:
Spinal cord dilates pupil

Submandibular
and sublingual
glands

Parotid gland

(/)
-0
c
T1
<ll
c;,
(ij
Q)
;: Heart
(/)
-0
c
<ll
(/) .
..91
0
(/)
:J
E
0
0
E Bronchial tree
.Q
·a.
J!)..
Q)

~
Q)
>
-0
0
0
:0
0
f- Stomach

Small intestine

L3
Large intestine

Male genitalia

Sympathetic Sympathetic
chain chain

Fig. 2.2 Innervation of the sympathet ic nervous syst em. Preganglionic neurons originate
in thoracic and lumbar segments of the spinal cord CT1-L3l.
 2—Autonomic Nervous System • 51

ganglia, the preganglionic neurons synapse on postgan- with nicotinic (N2) receptors on the cell bodies of
glionic neurons, which travel to the periphery and postganglionic neurons. Postganglionic neurons of the
innervate the effector organs. sympathetic division are adrenergic in all of the effector
The features of the sympathetic nervous system organs, except in the thermoregulatory sweat glands
discussed in the following sections are listed in Table (where they are cholinergic). The effector organs that
2.1 and are illustrated in Figure 2.2. are innervated by sympathetic adrenergic neurons
have one or more of the following types of adreno-
Origin of Preganglionic Neurons receptors: alpha1, alpha2, beta1, or beta2 (α1, α2, β1,
The preganglionic neurons of the sympathetic division or β2). The thermoregulatory sweat glands innervated
arise from nuclei in the thoracic and lumbar spinal cord by sympathetic cholinergic neurons have muscarinic
segments, specifically from the first thoracic segment cholinoreceptors.
to the third lumbar segment (T1–L3). Thus the sympa-
thetic division is referred to as thoracolumbar. Sympathetic Adrenergic Varicosities
Generally, the origin of preganglionic neurons in the As described previously, sympathetic postganglionic
spinal cord is anatomically consistent with the projec- adrenergic nerves release their neurotransmitters from
tion to the periphery. Thus the sympathetic pathways varicosities onto their target tissues (e.g., vascular
to organs in the thorax (e.g., heart) have preganglionic smooth muscle). The sympathetic adrenergic varicosi­
neurons originating in the upper thoracic spinal cord. ties contain both the classic neurotransmitter (norepi-
Sympathetic pathways to organs in the pelvis (e.g., nephrine) and nonclassic neurotransmitters (adenosine
colon, genitals) have preganglionic neurons that origi- triphosphate [ATP] and neuropeptide Y). The classic
nate in the lumbar spinal cord. Blood vessels, thermo- neurotransmitter, norepinephrine, is synthesized from
regulatory sweat glands, and pilomotor muscles of the tyrosine in the varicosities (see Fig. 1.18) and stored in
skin have preganglionic neurons that synapse on small dense-core vesicles, ready for release; these
multiple postganglionic neurons up and down the small dense-core vesicles also contain dopamine
sympathetic chain, reflecting their broad distribution β-hydroxylase, which catalyzes the conversion of dopa-
throughout the body. mine to norepinephrine (the final step in the synthetic
pathway), and ATP. ATP is said to be “colocalized”
Location of Autonomic Ganglia with norepinephrine. A separate group of large dense-
The ganglia of the sympathetic nervous system are core vesicles contain neuropeptide Y.
located near the spinal cord, either in the paravertebral When sympathetic postganglionic adrenergic
ganglia (known as the sympathetic chain) or in the neurons are stimulated, norepinephrine and ATP are
prevertebral ganglia. Again, the anatomy is logical. released from the small dense-core vesicles. Both nor-
The superior cervical ganglion projects to organs in the epinephrine and ATP serve as neurotransmitters at the
head such as the eyes and the salivary glands. The neuroeffector junction, binding to and activating their
celiac ganglion projects to the stomach and the small respective receptors on the target tissue (e.g., vascular
intestine. The superior mesenteric ganglion projects to smooth muscle). Actually, ATP acts first, binding to
the small and large intestine, and the inferior mesen- purinergic receptors on the target tissue and causing
teric ganglion projects to the lower large intestine, a physiologic effect (e.g., contraction of the vascular
anus, bladder, and genitalia. smooth muscle). The action of norepinephrine follows
The adrenal medulla is simply a specialized sympa- ATP; norepinephrine binds to its receptors on the
thetic ganglion whose preganglionic neurons originate target tissue (e.g., α1-adrenergic receptors on vascular
in the thoracic spinal cord (T5–T9), pass through the smooth muscle) and causes a second, more prolonged
sympathetic chain and the celiac ganglion without contraction. Finally, with more intense or higher-
synapsing, and travel in the greater splanchnic nerve frequency stimulation, the large dense-core vesicles
to the adrenal gland. release neuropeptide Y, which binds to its receptor
on the target tissue, causing a third, slower phase of
Length of Preganglionic and contraction.
Postganglionic Axons
Because the sympathetic ganglia are located near the Adrenal Medulla
spinal cord, the preganglionic nerve axons are short The adrenal medulla is a specialized ganglion in the
and the postganglionic nerve axons are long (so that sympathetic division of the autonomic nervous system.
they can reach the peripheral effector organs). The cell bodies of its preganglionic neurons are located
in the thoracic spinal cord. The axons of these pre-
Neurotransmitters and Types of Receptors ganglionic neurons travel in the greater splanchnic
Preganglionic neurons of the sympathetic division are nerve to the adrenal medulla, where they synapse on
always cholinergic. They release ACh, which interacts chromaffin cells and release ACh, which activates
52 • Physiology

nicotinic receptors. When activated, the chromaffin mainly epinephrine, a pheochromocytoma secretes
cells of the adrenal medulla secrete catecholamines mainly norepinephrine, which is explained by the fact
(epinephrine and norepinephrine) into the general that the tumor is located too far from the adrenal cortex
circulation. In contrast with sympathetic postganglionic to receive the cortisol that is required by PNMT.
neurons, which release only norepinephrine, the adrenal
medulla secretes mainly epinephrine (80%) and a Fight or Flight Response
small amount of norepinephrine (20%). The reason for The body responds to fear, extreme stress, and intense
this difference is the presence of phenylethanolamine- exercise with a massive, coordinated activation of the
N-methyltransferase (PNMT) in the adrenal medulla sympathetic nervous system including the adrenal
but not in sympathetic postganglionic adrenergic medulla. This activation, the fight or flight response,
neurons (see Fig. 1.18). PNMT catalyzes the conversion ensures that the body can respond appropriately to a
of norepinephrine to epinephrine, a step that, interest- stressful situation (e.g., take a difficult exam, run away
ingly, requires cortisol from the nearby adrenal cortex; from a burning house, fight an attacker). The response
cortisol is supplied to the adrenal medulla in venous includes increases in heart rate, cardiac output, and
effluent from the adrenal cortex. blood pressure; redistribution of blood flow away from
A tumor of the adrenal medulla, or pheochromocy- skin, kidneys, and splanchnic regions and toward
toma, may be located on or near the adrenal medulla, skeletal muscle; increased ventilation, with dilation
or at a distant (ectopic) location in the body (Box 2.1). of the airways; decreased gastrointestinal motility and
Unlike the normal adrenal medulla, which secretes secretions; and increased blood glucose concentration.

BOX 2.1 Cllnlcal Physiology: Pheochromocytoma

DESCRIPTION OF CASE. A 48-year-old woman visits activated by the increased levels of epinephrine and
her physician complaining of what she calls "panic norepinephrine, which reach the tissues via the circula-
attacks." She reports that she has experienced a racing tion. The woman's most prominent symptoms are
heart and that she can feel (and even see) her heart cardiovascular: pounding heart, increased heart rate,
pounding in her chest. She also complains of throbbing increased blood pressure, and cold hands and feet.
headaches, cold hands and cold feet, feeling hot, visual These symptoms can be understood by considering the
disturbances, and nausea and vomiting. In the physi- functions of adrenoreceptors in the heart and blood
cian's office, her blood pressure is severely elevated vessels. The increased amounts of circulating catechol-
(230/125). She is admitted to the hospital for evalua- amines activated ~1 receptors in the heart, increasing
tion of her hypertension. the heart rate and increasing contractility (pounding of
A 24-hour urine sample reveals elevated levels of the heart). Activation of a1receptors in vascular smooth
metanephrine, normetanephrine, and 3-methoxy-4- muscle of the skin produced vasoconstriction, which
hydroxymandelic acid (VMA). After the physician rules presented as cold hands and feet. The patient felt hot,
out other causes for hypertension, he concludes that however, because this vasoconstriction in the skin
she has a tumor of the adrenal medulla, called a pheo- impaired the ability to dissipate heat. Her extremely
chromocytoma. A computerized tomographic scan of elevated blood pressure was caused by the combination
the abdomen reveals a 3.5-cm mass on her right adrenal of increased heart rate, increased contractility, and
medulla. The patient is administered an a 1 antagonist, increased constriction (resistance) of the blood vessels.
and surgery is performed. The woman recovers fully; The patient's headache was secondary to her elevated
her blood pressure returns to normal, and her other blood pressure.
symptoms disappear. The woman's other symptoms also can be explained
by the activation of adrenoreceptors in other organ
EXPLANATION OF CASE. The woman has a classic
systems (i.e., gastrointestinal symptoms of nausea and
pheochromocytoma, a tumor of the chromaffin cells of
vomiting and visual disturbances).
the adrenal medulla. The tumor secretes excessive
amounts of norepinephrine and epinephrine, which TREATMENT. The patient's treatment consisted of
produce all of the woman's symptoms and result in locating and excising the tumor, thereby removing the
elevated levels of catecholamine metabolites in her source of excess catecholamines. Alternatively, if the
urine. In contrast to normal adrenal medulla, which tumor had not been excised, the woman could have
secretes mainly epinephrine, pheochromocytomas been treated pharmacologically with a combination of
secrete mainly norepinephrine. a1 antagonists (e.g., phenoxybenzamine or prazosin)
The patient's symptoms can be interpreted by under- and ~1 antagonists (e.g., propranolol) to prevent the
standing the physiologic effects of catecholamines. actions of the endogenous catecholamines at the recep-
Any tissue where adrenoreceptors are present will be tor level.
 2-Autonomic Neroous System • 53

TABLE 2.2 Prototypes of Agonlsts and Antagonists to

Parasympathetic Nervous system Autonomic Receptors
The overall function of the parasympathetic nervous
Receptor Agonists Antagonists
system is restorative, to conserve energy. Figure 2.3
depicts the organization of the parasympathetic nervous Adrenoreceptors
system in relation to the CNS (brain stem and spinal cx1 Norepinephrine Phenoxybenzamine
cord), the parasympathetic ganglia, and the effector Phenylephrine Prazosin
organs. Preganglionic neurons of the parasympathetic Clonidine Yohimbine
division have their cell bodies in either the brain stem
Norepinephrine Propranolol
(midbrain, pons, and medulla) or the sacral spinal
Epinephrine Metoprolol
cord. Preganglionic axons project to a series of ganglia Isoproterenol
located near or in the effector organs. Dobutamine
The following features of the parasympathetic
Epinephrine Propranolol
nervous system can be noted and compared with the Norepinephrine Butoxamine
sympathetic nervous system (see Table 2.1 and Isoproterenol
Fig. 2.3). Albuterol

Origin of Preganglionic Neurons Cholinoreceptors

Preganglionic neurons of the parasympathetic division Nicotinic ACh Curare (blocks
arise from nuclei of cranial nerves (CNs) III, VII, IX, Nicotine neuromuscular N1
and X or from sacral spinal cord segments S2-S4; receptors)
Hexamethonium
therefore the parasympathetic division is called cranio-
(blocks ganglionic
sacral. As in the sympathetic division, the origin of N2 receptors)
the preganglionic neurons in the CNS is consistent
Muscarinic ACh Atropine
with the projection to effector organs in the periphery.
Muscarine
For example, the parasympathetic innervation of eye
muscles originates in the Edinger-Westphal nucleus in ACh, Acetylcholine.
the midbrain and travels to the periphery in CN III; the
parasympathetic innervation of the heart, bronchioles,
and gastrointestinal tract originates in nuclei of the
medulla and travels to the periphery in CN X (vagus postganglionic neurons. Most postganglionic neurons
nerve); and the parasympathetic innervation of the of the parasympathetic division are also cholinergic.
genitourinary organs originates in the sacral spinal cord Receptors for ACh in the effector organs are muscarinic
and travels to the periphery in the pelvic nerves. receptors rather than nicotinic receptors. Thus ACh
released from preganglionic neurons of the para-
Location of Autonomic Ganglia sympathetic division activates nicotinic receptors,
In contrast to the sympathetic ganglia, which are whereas ACh released from postganglionic neurons of
located near the CNS, the ganglia of the parasympa- the parasympathetic division activates muscarinic
thetic nervous system are located near, on, or in the receptors. These receptors and their functions are
effector organs (e.g., ciliary, pterygopalatine, subman- distinguished by the drugs that activate or inhibit
dibular, otic). them (Table 2.2).

Length of Preganglionic and Postganglionic Axons Parasympathetic Cholinergic Varicosities

The relative length of preganglionic and postganglionic As described previously, parasympathetic postgangli-
axons in the parasympathetic division is the reverse of onic cholinergic nerves release their neurotransmitters
the relative lengths in the sympathetic division. This from varicosities onto their target tissues (e.g., smooth
difference reflects the location of the ganglia. The muscle). The parasympathetic cholinergic varicosities
parasympathetic ganglia are located near or in the release both the classic neurotransmitter (ACh) and
effector organs; therefore the preganglionic neurons nonclassic neurotransmitters (e.g., vasoactive intestinal
have long axons and the postganglionic neurons have peptide [VIP], NO). The classic neurotransmitter, ACh,
short axons. is synthesized in the varicosities from choline and
acetyl coenzyme A (acetyl CoA) (see Fig. 1.17) and
Neurotransmitters and Types of Receptors stored in small, clear vesicles. A separate group of
As in the sympathetic division, all preganglionic large dense-core vesicles contains peptides such as
neurons are cholinergic and release ACh, which inter- VIP. Lastly, the varicosities contain nitric oxide syn-
acts at nicotinic (N2) receptors on the cell bodies of thase and can synthesize NO on demand.
54 • Physiology

PARASYMPATHETIC NERVOUS SYSTEM

Circular muscle:
constricts pupil
Midbrain SEdinger-Westphal
]3ucleus - - - - --l--1 Ciliary muscle:
near vision

t
lacrimal nucleus
Pons Superior salivatory
nucleus-- - ---l-1 Lacrimal and
nasal glands
nferior salivatory
nucleus - -- - - - - 1 ' - -- - l Submandibular
Medulla and sublingual
{ Dorsal motor nucleus glands
of vagal nerve
Parotid gland

Heart
CNX

Bronchial tree

Stomach

Spinal cord
Small intestine

Large intestine

82 Urinary bladder

83

84
Male genitalia

Fig. 2.3 Innervation of the parasympathetic nervous system. Preganglionic neurons

originate in nuclei of the brain stem <midbrain, pons, medullal and in sacral segments !S2- S4l of
the spinal cord. CN, Cranial nerve.
 2—Autonomic Nervous System • 55

When parasympathetic postganglionic cholinergic sympathetic and parasympathetic innervations, which

neurons are stimulated, ACh is released from the vari- function reciprocally to modulate the heart rate. Thus
cosities and binds to muscarinic receptors on the target an increase in sympathetic activity increases heart rate,
tissue, which direct its physiologic action. With intense and an increase in parasympathetic activity decreases
or high-frequency stimulation, the large dense-core heart rate. These reciprocal functions are illustrated
vesicles release their peptides (e.g., VIP), which bind as follows: If there is a decrease in blood pressure,
to receptors on the target tissues and augment the vasomotor centers in the brain stem respond to this
actions of ACh. decrease and produce, simultaneously, an increase in
sympathetic activity to the SA node and a decrease
in parasympathetic activity. Each of these actions,
Autonomic Innervation of the Organ Systems
directed and coordinated by the brain stem vasomotor
Table 2.3 serves as a reference for information concern- center, has the effect of increasing heart rate. The sym-
ing autonomic control of organ system function. This pathetic and parasympathetic actions do not compete
table lists the sympathetic and parasympathetic inner- with each other but work synergistically to increase
vations of the major organ systems and the receptor the heart rate (which helps restore normal blood
types that are present in these tissues. Table 2.3 will be pressure).
most valuable if the information it contains is seen as
a set of recurring themes rather than as a random list URINARY BLADDER
of actions and receptors. The urinary bladder is another example of reciprocal
innervations by sympathetic and parasympathetic divi-
Reciprocal Functions—Sympathetic sions (Fig. 2.4). In adults, micturition, or emptying of
and Parasympathetic the bladder, is under voluntary control because the
Most organs have both sympathetic and parasympa- external sphincter is composed of skeletal muscle.
thetic innervation. These innervations operate recip­ However, the micturition reflex itself is controlled by
rocally or synergistically to produce coordinated the autonomic nervous system. This reflex occurs when
responses. For example, the heart has both sympathetic the bladder is sensed as being “full.” The detrusor
and parasympathetic innervations that function recip- muscle of the bladder wall and the internal bladder
rocally to regulate heart rate and conduction velocity. sphincter are composed of smooth muscle; each has
The smooth muscle walls of the gastrointestinal tract both sympathetic and parasympathetic innervations.
and the bladder have both sympathetic innervation The sympathetic innervation of the detrusor muscle
(which produces relaxation) and parasympathetic and the internal sphincter originates in the lumbar
innervation (which produces contraction); the sphinc- spinal cord (L1–L3), and the parasympathetic innerva-
ters of the gastrointestinal tract and the bladder also tion originates in the sacral spinal cord (S2–S4).
have both sympathetic innervation (which produces When the bladder is filling with urine, sympathetic
contraction) and parasympathetic innervation (which control predominates. This sympathetic activity pro-
produces relaxation). The radial muscles of the iris are duces relaxation of the detrusor muscle, via β2 recep-
responsible for dilation of the pupil (mydriasis) and tors, and contraction of the internal sphincter muscle,
have sympathetic innervation; the circular muscle of via α1 receptors. The external sphincter is simultane-
the iris is responsible for constriction of the pupil ously closed by trained voluntary action. When the
(miosis) and has parasympathetic innervation. In this muscle wall is relaxed and the sphincters are closed,
example of the eye muscles, different muscles control the bladder can fill with urine.
pupil size, but the overall effects of sympathetic and When the bladder is full, this fullness is sensed by
parasympathetic activity are reciprocal. In the male mechanoreceptors in the bladder wall, and afferent
genitalia, sympathetic activity controls ejaculation and neurons transmit this information to the spinal cord
parasympathetic activity controls erection, which, and then to the brain stem. The micturition reflex is
together, are responsible for the male sexual response. coordinated by centers in the midbrain, and now para­
The following three examples further illustrate the sympathetic control predominates. Parasympathetic
reciprocity and synergism of the sympathetic and activity produces contraction of the detrusor muscle (to
parasympathetic divisions. increase pressure and eject urine) and relaxation of
the internal sphincters. Simultaneously, the external
SINOATRIAL NODE sphincter is relaxed by a voluntary action.
The autonomic innervation of the sinoatrial (SA) Clearly, the sympathetic and parasympathetic actions
node in the heart is an excellent example of coordi- on the bladder structures are opposite but coordinated:
nated control of function. The SA node is the normal The sympathetic actions dominate for bladder filling,
pacemaker of the heart, and its rate of depolarization and the parasympathetic actions dominate for bladder
determines the overall heart rate. The SA node has both emptying.
 2- Autonomic Nervous System • 57

Filling of Bladder Emptying of Bladder

Control Control
Muscle State State
Mechanism Mechanism
Spinal cord

L1 Sympathetic
L2
L3 ·········::::: ·····<® /Detrusor
muscle
Relaxed Sympathetic

@
Contracted Parasympathetic

/Internal Contracted Sympathetic Relaxed Parasympathetic

sphincter
S2 @ @
S3
S4

• • ~External Contracted Voluntary Relaxed Voluntary

sphincter

Fig. 2.4 Autonomic control of bladder f unction. During filling of the bladder, sympathetic
control predominates. causing relaxation of the detrusor muscle and contraction of the internal
sphincter. During micturition. parasympathetic control predominates, causing contraction of the
detrusor muscle and relaxation of the internal sphincter. Dashed Jines represent sympathetic
innervation; solid lines represent parasympathetic innervation. a,, Adrenoreceptor in internal
sphincter; /Ji. adrenoreceptor in detrusor muscle; L1- L3, lumbar segments; M, muscarinic cholino-
receptor in detrusor muscle and internal sphincter; 52- 54, sacral segments.

Activation of these muscarinic receptors causes con- activity of the detrusor muscle in the bladder wall and
striction of the sphincter muscle, which causes con- in the sphincters (see Fig. 2.4). Thus sympathetic activ-
striction of the pupil, or miosis. ity dominates when the bladder is filling to produce
For example, in the pupillary light reflex, light relaxation of the bladder wall and, simultaneously,
strikes the retina and, through a series of CNS connec- contraction of the internal bladder sphincter. The
tions, activates parasympathetic preganglionic nerves bladder can fill because the bladder wall is relaxed and
in the Edinger-Westphal nucleus; activation of these the sphincter is closed. During micturition, parasympa-
parasympathetic fibers causes contraction of the thetic activity dominates, producing contraction of the
sphincter muscle and pupillary constriction. In the bladder wall and, simultaneously, relaxation of the
accommodation response, a blurred retinal image sphincter.
activates parasympathetic preganglionic neurons in the Similar reasoning can be applied to the autonomic
Edinger-Westphal nuclei and leads to contraction of control of the gastrointestinal tract: Contraction of the
the sphincter muscle and pupillary constriction. At the wall of the gastrointestinal tract is accompanied by
same time, the ciliary muscle contracts, causing the relaxation of the sphincters (parasympathetic), allow-
lens to "round up" and its refractive power to increase. ing the contents of the gastrointestinal tract to be
There are some notable exceptions to the generaliza- propelled forward. Relaxation of the wall of the
tion of reciprocal innervation. Several organs have only gastrointestinal tract is accompanied by contraction of
sympathetic innervation: sweat glands, vascular the sphincters (sympathetic); the combined effect of
smooth muscle, pilomotor muscles of the skin, liver, these actions is to slow or stop movement of the
adipose tissue, and kidney. contents.

Coordination of Function Within Organs Types of Receptors

Coordination of function within the organ systems, Inspection of Table 2.3 permits some generalizations
as orchestrated by the autonomic nervous system, about types of receptors and their mechanisms of
is another recurring physiologic theme (Boxes 2.2 action. These generalizations are as follows: (1) In the
and 2.3). parasympathetic division, effector organs have musca-
This control is exquisitely clear, for example, when rinic receptors. (2) In the sympathetic division, there
considering the function of the urinary bladder. In this are multiple receptor types in effector organs including
organ, there must be a timely coordination between the four adrenoreceptors (<X1> cx2 , ~1> ~2); and in tissues
 2-Autonomic Nervous System • 59

with sympathetic cholinergic innervation, there are compares this information to a blood pressure set point.
muscarinic receptors. (3) Among the sympathetic If corrections are necessary, the vasomotor center
adrenoreceptors, receptor type is related to function. orchestrates changes in output of both the sympathetic
The cx1 receptors cause contraction of smooth muscle and the parasympathetic innervation of the heart and
such as vascular smooth muscle, gastrointestinal and blood vessels to bring about the necessary change in
bladder sphincters, pilomotor muscles, and the radial blood pressure. These higher autonomic centers are
muscle of the iris. The ~ 1 receptors are involved in discussed throughout this book in the context of each
metabolic functions such as gluconeogenesis, lipolysis, organ system.
renin secretion, and in all functions in the heart. The
~ 2 receptors cause relaxation of smooth muscle in
bronchioles, wall of the bladder, and wall of the AUTONOMIC RECEPTORS
gastrointestinal tract.
As noted in the preceding discussion, autonomic recep-
tors are present at the neuromuscular junction, on the
Hypothalamic and Brain Stem centers cell bodies of postganglionic neurons, and in the effec-
Centers in the hypothalamus and brain stem coordinate tor organs. The type of receptor and its mechanism of
the autonomic regulation of organ system functions. action determine the nature of the physiologic response.
Figure 2.5 summarizes the locations of these centers, Furthermore, the physiologic responses are tissue spe-
which are responsible for temperature regulation, thirst, cific and cell type specific.
food intake (satiety), micturition, breathing, and car- To illustrate this specificity, compare the effect
diovascular (vasomotor) function. For example, the of activating adrenergic ~ 1 receptors in the SA node
vasomotor center receives information about blood to the effect of activating ~ 1 receptors in ventricular
pressure from baroreceptors in the carotid sinus and muscle. Both the SA node and the ventricular muscle

Hypothalamus

Temperature
regulation
Thirst
Midbrain Food intake

Pons
---t--- Pneumotaxic center

T---- Vasomotor center

(cardiovascular)
Medulla
Respiratory center

Swallowing, coughing,
vomiting centers

Spinal cord

Fig. 2.5 Autonomic centers in the hypothalamus and brain stem.

a, First cervical spinal cord segment.
60 • Physiology

are located in the heart, and their adrenergic receptors active state; when GTP is converted back to GDP
and mechanisms of action are the same. The resulting through intrinsic GTPase activity of the G protein, it
physiologic actions, however, are entirely different. The switches from the active state to the inactive state.
β1 receptor in the SA node is coupled to mechanisms G proteins couple G protein–linked autonomic
that increase the spontaneous rate of depolarization receptors to enzymes that execute physiologic actions.
and increase heart rate; binding of an agonist such These enzymes are adenylyl cyclase and phospholipase
as norepinephrine to this β1 receptor increases the C, which, when activated, generate a second messen-
heart rate. The β1 receptor in ventricular muscle is ger (cyclic adenosine monophosphate [cAMP] or IP3,
coupled to mechanisms that increase intracellular Ca2+ respectively). The second messenger then amplifies the
concentration and contractility; binding of an agonist message and executes the final physiologic action. In
such as norepinephrine to this β1 receptor increases some cases (e.g., certain muscarinic receptors), the G
contractility, but it has no direct effect on the heart rate. protein directly alters the function of an ion channel
The type of receptor also predicts which pharmaco- without the mediation of a second messenger.
logic agonists or antagonists will activate it or block it.
The effects of such drugs can be readily predicted by
Adrenoreceptors
understanding the normal physiologic responses. For
example, drugs that are β1 agonists are expected to Adrenoreceptors are found in target tissues of the
cause increased heart rate and increased contractility, sympathetic nervous system and are activated by the
and drugs that are β1 antagonists are expected to cause catecholamines norepinephrine and epinephrine. Nor-
decreased heart rate and decreased contractility. epinephrine is released from postganglionic neurons of
Table 2.4 summarizes the features of adrenergic the sympathetic nervous system. Epinephrine is secreted
and cholinergic receptors, their target tissues, and by the adrenal medulla and reaches the target tissues
their mechanisms of action. Table 2.2, its companion, via the circulation. Adrenoreceptors are divided into
is arranged similarly by receptor type and lists the two types, α and β, which are further designated as α1,
prototypical drugs that either activate (agonists) or α2, β1, and β2 receptors. Each of the receptor types has
block (antagonists) the receptors. Together, the two a different mechanism of action (except the β1 and β2
tables should be used as a reference for the following receptors, which have the same mechanism of action),
discussion about mechanisms of action. These mecha- resulting in different physiologic effects (see Tables 2.3
nisms involving guanosine triphosphate (GTP)–binding and 2.4).
proteins (G proteins), adenylyl cyclase, and inositol
1,4,5-triphosphate (IP3) also are discussed in Chapter 9 α1 Receptors
in the context of hormone action. 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,
G Proteins
and in the radial muscle of the iris. Activation of α1
Autonomic receptors are coupled to GTP-binding pro- receptors leads to contraction in each of these tissues.
teins (G proteins) and therefore are called G protein– The mechanism of action involves a G protein called
linked receptors. G protein–linked receptors, including Gq and activation of phospholipase C, illustrated in
those in the autonomic nervous system, are composed Figure 2.6. The circled numbers in the figure correspond
of a single polypeptide chain that winds back and forth to the steps discussed as follows:
across the cell membrane seven times; thus they are
also known as seven-pass transmembrane receptor 1. The α1 receptor is embedded in the cell membrane,
proteins. The ligand (e.g., ACh, norepinephrine) binds where it is coupled, via the Gq protein, to phospho-
to the extracellular domain of its G protein–linked lipase C. In the inactive state, the αq subunit of the
receptor. The intracellular domain of the receptor binds heterotrimeric Gq protein is bound to GDP.
to (is “linked” to) a G protein.
2. When an agonist such as norepinephrine binds to
These G proteins are heterotrimeric. In other words,
the α1 receptor (Step 1), a conformational change
they have three different subunits: α, β, and γ. The α
occurs in the αq subunit of the Gq protein. This
subunit binds either guanosine diphosphate (GDP) or
conformational change has two effects (Step 2): GDP
GTP. When GDP is bound, the α subunit is inactive;
is released from the αq subunit and replaced by GTP,
when GTP is bound, the α subunit is active. Thus
and the αq subunit (with GTP attached) detaches
activity of the G protein resides in its α subunit, and
from the rest of the Gq protein.
the G protein switches between active and inactive
states according to whether it is bound to GDP or GTP. 3. The αq-GTP complex migrates within the cell mem-
For example, when the G protein releases GDP and brane and binds to and activates phospholipase C
binds GTP, it switches from the inactive state to the (Step 3). Intrinsic GTPase activity then converts GTP
 2-Autonomic Neroous System • 61

TABLE 2.4 Location and Mechanism of Action of Autonomic Receptors

Receptor Target Tissue Mechanism of Action

Adrenoreceptors
Vascular smooth muscle, skin, renal, and splanchnic IP3, i intracellular [Ca2•]
Gastrointestinal tract, sphincters
Bladder, sphincter
Radial muscle, iris
Gastrointestinal tract, wall Inhibition of adenylyl cyclase, J. cAMP
Presynaptic adrenergic neurons
Heart Stimulation of adenylyl cyclase, i cAMP
Salivary glands
Adipose tissue
Kidney
Vascular smooth muscle of skeletal muscle Stimulation of adenylyl cyclase, i cAMP
Gastrointestinal tract, wall
Bladder, wall
Bronchioles
Cholinoreceptors
Nicotinic Skeletal muscle, motor end plate (N1) Opening Na• and K+ channels~
Postganglionic neurons, SNS and PNS (N2) depolarization
Adrenal medulla (N2)
Muscarinic All effector organs, PNS IP3, i intracellular [Ca2•] (Mi, M3 , M5)
Sweat glands, SNS J. adenylyl cyclase, J. cAMP (M2, M4)
cAMP, Cyclic adenosine monophosphate; IP~, inositol 1,4,5-triphosphate; PNS, parasympathetic nervous system; SNS, sympathetic nervous
system.

back to GDP, and the C:Xq subunit returns to the further release of norepinephrine from the same termi-
inactive state (not shown). nals; this negative feedback conserves norepinephrine
in states of high stimulation of the sympathetic nervous
4. Activated phospholipase C catalyzes the liberation
system. Interestingly, the adrenal medulla does not
of diacylglycerol and IP 3 from phosphatidylinositol
have cx2 receptors and therefore is not subject to feed-
4,5-diphosphate (Step 4). The IP3 that is generated
back inhibition; consequently, the adrenal medulla can
causes the release of Ca2+ from intracellular stores in
become depleted of catecholamines during periods of
the endoplasmic or sarcoplasmic reticulum, result-
prolonged stress.
ing in an increase in intracellular Ca 2+ concentration
cx.i Receptors present on parasympathetic postgangli-
(Step 5). Together, Ca2+ and diacylglycerol activate
onic nerve terminals of the gastrointestinal tract are
protein kinase C (Step 6), which phosphorylates
called heteroreceptors. Norepinephrine is released
proteins. These phosphorylated proteins execute the
from sympathetic postganglionic fibers that synapse on
final physiologic actions (Step 7) such as contraction
these parasympathetic postganglionic fibers. When
of smooth muscle.
activated by norepinephrine, the cx2 receptors cause
inhibition of release of ACh from the parasympathetic
ai Receptors postganglionic nerve terminals. In this way, the sym-
cx.i Receptors are inhibitory, are located both presynapti- pathetic nervous system indirectly inhibits gastro-
cally and postsynaptically, and are less common than intestinal function (i.e., by inhibiting the parasympathetic
cx1 receptors. They are found on presynaptic adrenergic activity).
and cholinergic nerve terminals and in the gastro- The mechanism of action of these receptors involves
intestinal tract. cx2 Receptors are found in two forms, the inhibition of adenylyl cyclase, described by the
autoreceptors and heteroreceptors. following steps:
cx.i Receptors present on sympathetic postganglionic
nerve terminals are called autoreceptors. In this func- 1. The agonist (e.g., norepinephrine) binds to the cx2
tion, activation of cx2 receptors by norepinephrine receptor, which is coupled to adenylyl cyclase by an
released from presynaptic nerve terminals inhibits inhibitory G protein, Gj.
62 • Physiology

a1 RECEPTORS

Norepinephrine •

Inactive a 1 Receptor
- Gqprotein
- phospholipase C

Norepinephrine • G)
Active a1 Receptor
- Gqprotein
- phospholipase C

IP3

®1"--'\t~*-
t protein kinase C from ER or SR

01
(Physiologic actions)

Fig. 2.6 Mechanism of action Of a, adrenoreceptors. In the inactive state, the aq subunit
of the Gq protein is bound to GDP. In the active state, with norepinephrine bound to the 0.1
receptor, the o.q subunit is bound to GTP. o.q, !}, and y 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; /~. inositol 1,4,5 -triphosphate; PJP2,
phosphatidylinositol 4,5-diphosphate; SR, sarcoplasmic reticulum.

2. When norepinephrine is bound, the G1 protein respectively. p1 Receptors also are located in the salivary
releases GDP and binds GTP, and the a. subunit glands, in adipose tissue, and in the kidney (where they
dissociates from the G protein complex. promote renin secretion). The mechanism of action of
3. The a. subunit then migrates in the membrane and
p1 receptors involves a G. protein and activation of
adenylyl cyclase. This action is illustrated in Figure 2. 7
binds to and inhibits adenylyl cyclase. As a result,
and involves the following steps, which correspond to
cAMP levels decrease, producing the final physiologic
the circled numbers in the figure:
action.
1. Similar to other autonomic receptors, p1 receptors
p., Receptors are embedded in the cell membrane. They are
p1 Receptors are prominent in the heart. They are coupled, via a G. protein, to adenylyl cyclase. In the
present in the SA node, in the atrioventricular (AV) inactive state, the ex. subunit of the G. protein is
node, and in ventricular muscle. Activation of p1 recep- bound to GDP.
tors in these tissues produces increased heart rate in
the SA node, increased conduction velocity in the AV 2. When an agonist such as norepinephrine binds to
node, and increased contractility in ventricular muscle, the p1 receptor (Step 1), a conformational change
 2- Autonomic Nervous System • 63

~1 AND ~2 RECEPTORS

Norepinephrine •

'"""" Fl - Gs protein
- adenylyl cyclase

Norepinephrine • Q)
Active
Fl - Gs protein
- adenylyl cyclase

cAMP

l®
Physiologic actions

Fig. 2.7 Mechanism of act ion Of ~ adrenoreceptors. In the inactive state, the as subunit of
the Gs protein is bound to GDP. In the active state, with norepinephrine bound to the ~ receptor,
the as subunit is bound to GTP. ~1 and ~2 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.

occurs in the a. subunit. This change has two effects When p1 receptors are activated in the SA node,
(Step 2): GDP is released from the a. subunit and heart rate increases; when p1 receptors are activated
replaced by GTP, and the activated a. subunit in ventricular muscle, contractility increases; when
detaches from the G protein complex. p1 receptors are activated in the salivary gland, secre-
tion increases; when p1 receptors are activated in the
3. The a.-GTP complex migrates within the cell mem- kidney, renin is secreted.
brane and binds to and activates adenylyl cyclase
(Step 3). GTPase activity converts GTP back to GDP,
and the a. subunit is returned to its inactive state Pi Receptors
(not shown). p2 Receptors are found in the vascular smooth muscle
of skeletal muscle, in the walls of the gastrointestinal
4. Activated adenylyl cyclase catalyzes the conversion tract and bladder, and in the bronchioles. The activa-
of ATP to cAMP, which serves as the second messen- tion of p2 receptors in these tissues leads to relaxation
ger (Step 4). cAMP, via steps involving activation of or dilation. The p2 receptors have a mechanism of
protein kinases, initiates the final physiologic actions action similar to that of p1 receptors: activation of a G.
(Step S). As mentioned previously, these physiologic protein, release of the a. subunit, stimulation of adeny-
actions are tissue specific and cell type specific. lyl cyclase, and generation of cAMP (see Fig. 2.7).
64 • Physiology

Responses of Adrenoreceptors to Norepinephrine can be answered by examining the actions of drugs that
and Epinephrine serve as agonists or antagonists to the nicotinic recep-
There are significant differences in the responses of α1, tor. The nicotinic receptors at the two loci are certainly
β1, and β2 adrenoreceptors to the catecholamines epi- similar: Both are activated by the agonists ACh, nico-
nephrine and norepinephrine. These differences are tine, and carbachol, and both are antagonized by the
explained as follows, recalling that norepinephrine is drug curare (see Table 2.2). However, another antago-
the catecholamine released from postganglionic sympa- nist to the nicotinic receptor, hexamethonium, blocks
thetic adrenergic nerve fibers, while epinephrine is the the nicotinic receptor in the ganglia but not the nicotinic
primary catecholamine released from the adrenal receptor on the motor end plate. Thus it can be con-
medulla: (1) Norepinephrine and epinephrine have cluded that the receptors at the two loci are similar but
almost the same potency at α1 receptors, with epineph- not identical, where the nicotinic receptor on the
rine being slightly more potent. However, compared skeletal muscle end plate is designated N1 and the nico-
with β receptors, α1 receptors are relatively insensitive tinic receptor in the autonomic ganglia is designated
to catecholamines. Higher concentrations of catechol- N2. This pharmacologic distinction predicts that drugs
amines are necessary to activate α1 receptors than to such as hexamethonium will be ganglionic-blocking
activate β receptors. Physiologically, such high concen- agents but not neuromuscular-blocking agents.
trations are reached locally when norepinephrine is A second conclusion can be drawn about ganglionic-
released from postganglionic sympathetic nerve fibers blocking agents such as hexamethonium. These agents
but not when catecholamines are released from the should inhibit nicotinic receptors in both sympathetic
adrenal medulla. For example, the amount of epineph- and parasympathetic ganglia, and thus they should
rine (and norepinephrine) released from the adrenal produce widespread effects on autonomic function.
medulla in the fight or flight response is insufficient to However, to predict the actions of ganglionic-blocking
activate α1 receptors. (2) Norepinephrine and epineph- agents on a particular organ system, it is necessary to
rine are equipotent at β1 receptors. As noted previously, know whether sympathetic or parasympathetic control
much lower concentrations of catecholamines will is dominant in that organ. For example, vascular
activate β1 receptors than will activate α1 receptors. smooth muscle has only sympathetic innervation,
Thus norepinephrine released from sympathetic nerve which causes vasoconstriction; thus ganglionic-blocking
fibers or epinephrine released from the adrenal medulla agents produce relaxation of vascular smooth muscle
will activate β1 receptors. (3) β2 receptors are preferen- and vasodilation. (Because of this property, ganglionic-
tially activated by epinephrine. Thus epinephrine blocking agents can be used to treat hypertension.) On
released from the adrenal medulla is expected to acti- the other hand, male sexual function is dramatically
vate β2 receptors, whereas norepinephrine released impaired by ganglionic-blocking agents because the
from sympathetic nerve endings is not. male sexual response has both sympathetic (ejacula-
tion) and parasympathetic (erection) components.
The mechanism of action of nicotinic receptors,
Cholinoreceptors
whether at the motor end plate or in the ganglia, is
There are two types of cholinoreceptors: nicotinic and based on the fact that this ACh receptor is also an ion
muscarinic. Nicotinic receptors are found on the motor channel for Na+ and K+. When the nicotinic receptor is
end plate, in all autonomic ganglia, and on chromaffin activated by ACh, the channel opens and both Na+ and
cells of the adrenal medulla. Muscarinic receptors are K+ flow through the channel, down their respective
found in all effector organs of the parasympathetic electrochemical gradients.
division and in a few effector organs of the sympathetic Figure 2.8 illustrates the function of the nicotinic
division. receptor/channel in two states: closed and open. The
nicotinic receptor is an integral cell membrane protein
Nicotinic Receptors consisting of five subunits: two α, one β, one delta
Nicotinic receptors are found in several important loca- (δ), and one gamma (γ). These five subunits form a
tions: on the motor end plate of skeletal muscle, on all funnel around the mouth of a central core. When no
postganglionic neurons of both sympathetic and para- ACh is bound, the mouth of the channel is closed.
sympathetic nervous systems, and on the chromaffin When ACh is bound to each of the two α subunits, a
cells of the adrenal medulla. ACh is the natural agonist, conformational change occurs in all of the subunits,
which is released from motoneurons and from all resulting in opening of the central core of the channel.
preganglionic neurons. When the core of the channel opens, Na+ and K+ flow
The question arises as to whether the nicotinic down their respective electrochemical gradients (Na+
receptor on the motor end plate is identical to the nico- into the cell, and K+ out of the cell), with each ion
tinic receptor in the autonomic ganglia. This question attempting to drive the membrane potential to its
 2- Autonomic Nervous System • 65

NICOTINI C RECEPTOR

Q Na+
Extracellular
fluid ••
••
•
y

~--- •• · ---------
••
O K+
Intracellular Channel cl osed Channel open
fluid

Fig. 2.8 Mechanism of act ion of nicotinic cholinoreceptors. The nicotinic receptor for
acetvlcholine <AChJ is an ion channel for Na· and K+. The receptor has five subunits: bNo ex, one ~.
one Ii, and one y.

equilibrium potential. The resulting membrane potential intracellular Ca2+ with diacylglycerol produces the
is midway between the Na+ and K+ equilibrium poten- tissue-specific physiologic actions.
tials, approximately 0 millivolts, which is a depolarized Other muscarinic receptors (e.g., MJ act by inhibit-
state. ing adenylyl cyclase and decreasing intracellular cAMP
levels.
Muscarinic Receptors Still other muscarinic receptors (M 2) alter physiologic
Muscarinic receptors are located in all of the effector processes via a direct action of the G protein. In these
organs of the parasympathetic nervous system: in the cases, no other second messenger is involved. For
heart, gastrointestinal tract, bronchioles, bladder, and example, muscarinic receptors in the cardiac SA node,
male sex organs. These receptors also are found in when activated by ACh, produce activation of a G;
certain effector organs of the sympathetic nervous protein and release of the a; subunit, which binds
system, specifically, in sweat glands. directly to K+ channels of the SA node. When the a;
Some muscarinic receptors (e.g., Mb M3 , and M5) subunits bind to K+ channels, the channels open,
have the same mechanism of action as the a 1 adreno- slowing the rate of depolarization of the SA node and
receptors (see Fig. 2.6). In these cases, binding of the decreasing the heart rate. In this mechanism, there is
agonist (ACh) to the muscarinic receptor causes dis- no stimulation or inhibition of either adenylyl cyclase
sociation of the a subunit of the G protein, activation or phospholipase C and no involvement of any second
of phospholipase C, and generation of IP3 and diacyl- messenger; rather, the G; protein acts directly on the
glycerol. IP 3 releases stored Ca2+, and the increased ion channel (Box 2.4).