Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 7

Neurotransmitters & Neuromodulators 135

nerve endings. Acetylcholine is then taken up into synaptic
vesicles by a vesicular transporter, VAChT.

Cholinesterases

Acetylcholine must be rapidly removed from the synapse if re-
polarization is to occur. The removal occurs by way of hydrol-
ysis of acetylcholine to choline and acetate, a reaction catalyzed
by the enzyme
acetylcholinesterase.
This enzyme is also called
true or specific cholinesterase. Its greatest affinity is for acetyl-
choline, but it also hydrolyzes other choline esters. There are a
variety of esterases in the body. One found in plasma is capable
of hydrolyzing acetylcholine but has different properties from
acetylcholinesterase. It is therefore called pseudocholinest-
erase or nonspecific cholinesterase. The plasma moiety is
partly under endocrine control and is affected by variations in
liver function. On the other hand, the specific cholinesterase
molecules are clustered in the postsynaptic membrane of cho-
linergic synapses. Hydrolysis of acetylcholine by this enzyme is
rapid enough to explain the observed changes in Na+ conduc-
tance and electrical activity during synaptic transmission.

Acetylcholine Receptors

Historically, acetylcholine receptors have been divided into
two main types on the basis of their pharmacologic proper-
ties. Muscarine, the alkaloid responsible for the toxicity of

toadstools, has little effect on the receptors in autonomic gan-

glia but mimics the stimulatory action of acetylcholine on

smooth muscle and glands. These actions of acetylcholine are

therefore called muscarinic actions, and the receptors in-

volved are muscarinic cholinergic receptors. They are

blocked by the drug atropine. In sympathetic ganglia, small

amounts of acetylcholine stimulate postganglionic neurons

and large amounts block transmission of impulses from

preganglionic to postganglionic neurons. These actions are

unaffected by atropine but mimicked by nicotine. Conse-

quently, these actions of acetylcholine are nicotinic actions

and the receptors are nicotinic cholinergic receptors. Nico-

tinic receptors are subdivided into those found in muscle at

neuromuscular junctions and those found in autonomic gan-

glia and the central nervous system. Both muscarinic and nic-

otinic acetylcholine receptors are found in large numbers in

the brain.

The nicotinic acetylcholine receptors are members of a

superfamily of ligand-gated ion channels that also includes the

GABAA and glycine receptors and some of the glutamate

receptors. They are made up of multiple subunits coded by dif-

ferent genes. Each nicotinic cholinergic receptor is made up of

five subunits that form a central channel which, when the

receptor is activated, permits the passage of Na+ and other cat-

ions. The 5 subunits come from a menu of 16 known subunits,

α 1 – α 9 , β 2 – β 5 , γ, δ, and ε, coded by 16 different genes. Some of

the receptors are homomeric—for example, those that contain

five α 7 subunits—but most are heteromeric. The muscle type

nicotinic receptor found in the fetus is made up of two α 1 sub-

units, a β 1 subunit, a γ subunit, and a δ subunit (Figure 7–5).

In adult mammals, the γ subunit is replaced by a δ subunit,

which decreases the channel open time but increases its

CLINICAL BOX 7–1

Excitotoxins

Glutamate is usually cleared from the brain’s extracellular

fluid by Na+-dependent uptake systems in neurons and

glia, keeping only micromolar levels of the chemical in the

extracellular fluid despite millimolar levels inside neurons.

However, excessive levels of glutamate occur in response

to ischemia, anoxia, hypoglycemia, or trauma. Glutamate

and some of its synthetic congeners are unique in that

when they act on neuronal cell bodies, they can produce so

much Ca2+ influx that neurons die. This is the reason why

microinjection of these excitotoxins is used in research to

produce discrete lesions that destroy neuronal cell bodies

without affecting neighboring axons. Evidence is accumu-

lating that excitotoxins play a significant role in the dam-

age done to the brain by a stroke. When a cerebral artery is

occluded, the cells in the severely ischemic area die. Sur-

rounding partially ischemic cells may survive but lose their

ability to maintain the transmembrane Na+ gradient. The

elevated levels of intracellular Na+ prevent the ability of as-

trocytes to remove glutamate from the brain’s extracellu-

lar fluid. Therefore, glutamate accumulates to the point

that excitotoxic damage and cell death occurs in the pen-

umbra, the region around the completely infarcted area.

FIGURE 7–4 Biochemical events at cholinergic endings. ACh,

acetylcholine; ASE, acetylcholinesterase; X, receptor.

Cholinergic

neuron

Postsynaptic

tissue

Acetyl-CoA

+

Choline

ACh

ACh

ASE

Choline