Ganong's Review of Medical Physiology, 23rd Edition

142 SECTION IIPhysiology of Nerve & Muscle Cells

the other hand, the GABAA receptors are pentamers made up
of various combinations of six α subunits, four β, four γ, one
δ, and one ε. This endows them with considerably different
properties from one location to another.
An observation of considerable interest is that there is a
chronic low-level stimulation of GABAA receptors in the CNS
that is aided by GABA in the interstitial fluid. This back-
ground stimulation cuts down on the “noise” caused by inci-
dental discharge of the billions of neural units and greatly
improves the signal-to-noise ratio in the brain. It may be that
this GABA discharge declines with advancing age, resulting in
a loss of specificity of responses of visual neurons. Support for
this hypothesis comes from studies in which microinjection
of GABA in older monkeys resulted in restoration of the spec-
ificity of visual neurons.
The increase in Cl– conductance produced by GABAA recep-
tors is potentiated by benzodiazepines, drugs that have marked
anti-anxiety activity and are also effective muscle relaxants,
anticonvulsants, and sedatives. Benzodiazepines bind to the α
subunits. Diazepam and other benzodiazepines are used
throughout the world. At least in part, barbiturates and alcohol
also act by facilitating Cl– conductance through the Cl– chan-
nel. Metabolites of the steroid hormones progesterone and
deoxycorticosterone bind to GABAA receptors and increase Cl–
conductance. It has been known for many years that progester-
one and deoxycorticosterone are sleep-inducing and anesthetic
in large doses, and these effects are due to their action on
GABAA receptors.
A second class of benzodiazepine receptors is found in ster-
oid-secreting endocrine glands and other peripheral tissues,
and hence these receptors are called peripheral benzodiaze-
pine receptors. They may be involved in steroid biosynthesis,

possibly performing a function like that of the StAR protein in

moving steroids into the mitochondria. Another possibility is

a role in the regulation of cell proliferation. Peripheral-type

benzodiazepine receptors are also present in astrocytes in the

brain, and they are found in brain tumors.

Glycine

Glycine has both excitatory and inhibitory effects in the CNS.

When it binds to NMDA receptors, it makes them more sen-

sitive. It appears to spill over from synaptic junctions into the

interstitial fluid, and in the spinal cord, for example, this gly-

cine may facilitate pain transmission by NMDA receptors in

the dorsal horn. However, glycine is also responsible in part

for direct inhibition, primarily in the brain stem and spinal

cord. Like GABA, it acts by increasing Cl– conductance. Its ac-

tion is antagonized by strychnine. The clinical picture of con-

vulsions and muscular hyperactivity produced by strychnine

emphasizes the importance of postsynaptic inhibition in nor-

mal neural function. The glycine receptor responsible for in-

hibition is a Cl– channel. It is a pentamer made up of two

subunits: the ligand-binding α subunit and the structural β

subunit. Recently, solid evidence has been presented that three

kinds of neurons are responsible for direct inhibition in the

spinal cord: neurons that secrete glycine, neurons that secrete

GABA, and neurons that secrete both. Presumably, neurons

that secrete only glycine have the glycine transporter GLYT2,

those that secrete only GABA have GAD, and those that se-

crete glycine and GABA have both. This third type of neuron

is of special interest because the neurons seem to have glycine

and GABA in the same vesicles.

FIGURE 7–10 Diagram of GABAA and GABAB receptors, showing their principal actions. The G protein that mediates the effects of
GABAB receptors is a heterodimer. (Reproduced with permission from Bowery NG, Brown DA: The cloning of GABAB receptors. Nature 1997;386:223. Copyright © 1997 by
Macmillan Magazines.)

AC

β α α

γ

β

γ

−

GABAA

Extracellular

Intracellular

Cl−

GABAB

NH 2

K+ Ca^2 +

COOH