Ganong's Review of Medical Physiology, 23rd Edition

136 SECTION IIPhysiology of Nerve & Muscle Cells

conductance. The nicotinic cholinergic receptors in autonomic
ganglia are heteromers that usually contain α 3 subunits in
combination with others, and the nicotinic receptors in the
brain are made up of many other subunits. Many of the nico-
tinic cholinergic receptors in the brain are located presynapti-
cally on glutamate-secreting axon terminals, and they facilitate
the release of this transmitter. However, others are postsynap-
tic. Some are located on structures other than neurons, and
some seem to be free in the interstitial fluid, that is, they are
perisynaptic in location.
Each α subunit has a binding site for acetylcholine, and
when an acetylcholine molecule binds to each of them, they
induce a confirmational change in the protein so that the
channel opens. This increases the conductance of Na+ and
other cations, and the resulting influx of Na+ produces a
depolarizing potential. A prominent feature of neuronal nico-
tinic cholinergic receptors is their high permeability to Ca2+.
Muscarinic cholinergic receptors are very different from
nicotinic cholinergic receptors. Five types, encoded by five
separate genes, have been cloned. The exact status of M 5 is
uncertain, but the remaining four receptors are coupled via G
proteins to adenylyl cyclase, K+ channels, and/or phospholi-
pase C (Table 7–2). The nomenclature of these receptors has
not been standardized, but the receptor designated M 1 in
Table 7–2 is abundant in the brain. The M 2 receptor is found
in the heart. The M 4 receptor is found in pancreatic acinar
and islet tissue, where it mediates increased secretion of pan-
creatic enzymes and insulin. The M 3 and M 4 receptors are
associated with smooth muscle.

Serotonin

Serotonin (5-hydroxytryptamine; 5-HT) is present in highest

concentration in blood platelets and in the gastrointestinal

tract, where it is found in the enterochromaffin cells and the

myenteric plexus. It is also found within the brain stem in the

midline raphé nuclei which project to portions of the hypo-

thalamus, the limbic system, the neocortex, the cerebellum,

and the spinal cord (Figure 7–2).

Serotonin is formed in the body by hydroxylation and

decarboxylation of the essential amino acid tryptophan (Fig-

ures 7–1 and 7–6). After release from serotonergic neurons,

much of the released serotonin is recaptured by an active

reuptake mechanism and inactivated by monoamine oxidase

(MAO) to form 5-hydroxyindoleacetic acid (5-HIAA). This

substance is the principal urinary metabolite of serotonin, and

urinary output of 5-HIAA is used as an index of the rate of

serotonin metabolism in the body.

Tryptophan hydroxylase in the human CNS is slightly differ-

ent from the tryptophan hydroxylase in peripheral tissues, and

is coded by a different gene. This is presumably why knockout

of the TPH1 gene, which codes for tryptophan hydroxylase in

peripheral tissues, has much less effect on brain serotonin pro-

duction than on peripheral serotonin production.

As described in Clinical Box 7–2, there is evidence for a

relationship between behavior and brain serotonin content.

Serotonergic Receptors

The number of cloned and characterized serotonin receptors

has increased rapidly. There are at least seven types of 5-HT

FIGURE 7–5 Three-dimensional model of the nicotinic acetylcholine-gated ion channel. The receptor–channel complex consists of
five subunits, all of which contribute to forming the pore. When two molecules of acetylcholine bind to portions of the α-subunits exposed to the
membrane surface, the receptor–channel changes conformation. This opens the pore in the portion of the channel emnbedded in the lipid bilayer,
and both K+ and Na+ flow through the open channel down their electrochemical gradient. (From Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of
Neural Science, 4th ed. McGraw-Hill, 2000.)

Na+

K+

ACh

No ACh bound:

Channel closed

Two ACh molecules bound:

Channel open