Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 7Neurotransmitters & Neuromodulators 141

DAG levels or decrease intracellular cAMP levels. Eleven sub-
types have been identified (Table 7–2). They are both presyn-
aptic and postsynaptic, and they are widely distributed in the
brain. They appear to be involved in the production of synap-
tic plasticity, particularly in the hippocampus and the cerebel-
lum. Knockout of the gene for one of these receptors, one of
the forms of mGluR1, causes severe motor incoordination and
deficits in spatial learning.
The ionotropic receptors are ligand-gated ion channels that
resemble nicotinic cholinergic receptors and GABA and glycine
receptors. There are three general types, each named for the
congeners of glutamate to which they respond in maximum
fashion. These are the kainate receptors (kainate is an acid iso-
lated from seaweed), AMPA receptors (for α-amino-3-
hydroxy-5-methylisoxazole-4-propionate), and NMDA recep-
tors (for N-methyl-D-aspartate). Four AMPA, five kainate, and
six NMDA subunits have been identified, and each is coded by
a different gene. The receptors were initially thought to be pen-
tamers, but some may be tetramers, and their exact stoichiome-
try is unsettled.
The kainate receptors are simple ion channels that, when
open, permit Na+ influx and K+ efflux. There are two popula-
tions of AMPA receptors: one is a simple Na+ channel and one
also passes Ca2+. The balance between the two in a given syn-
apse can be shifted by activity.
The NMDA receptor is also a cation channel, but it per-
mits passage of relatively large amounts of Ca2+, and it is
unique in several ways (Figure 7–9). First, glycine facilitates
its function by binding to it, and glycine appears to be essen-
tial for its normal response to glutamate. Second, when
glutamate binds to it, it opens, but at normal membrane
potentials, its channel is blocked by a Mg2+ ion. This block is
removed only when the neuron containing the receptor is
partially depolarized by activation of AMPA or other chan-
nels that produce rapid depolarization via other synaptic cir-
cuits. Third, phencyclidine and ketamine, which produce
amnesia and a feeling of dissociation from the environment,
bind to another site inside the channel. Most target neurons
for glutamate have both AMPA and NMDA receptors. Kain-
ate receptors are located presynaptically on GABA-secreting
nerve endings and postsynaptically at various localized sites
in the brain. Kainate and AMPA receptors are found in glia
as well as neurons, but it appears that NMDA receptors
occur only in neurons.
The concentration of NMDA receptors in the hippocampus
is high, and blockade of these receptors prevents long-term
potentiation, a long-lasting facilitation of transmission in
neural pathways following a brief period of high-frequency
stimulation. Thus, these receptors may well be involved in
memory and learning.

GABA

GABA is the major inhibitory mediator in the brain, includ-
ing being responsible for presynaptic inhibition. GABA,
which exists as β-aminobutyrate in the body fluids, is formed

by decarboxylation of glutamate (Figure 7–1). The enzyme

that catalyzes this reaction is glutamate decarboxylase

(GAD), which is present in nerve endings in many parts of

the brain. GABA is metabolized primarily by transamination

to succinic semialdehyde and thence to succinate in the citric

acid cycle. GABA transaminase (GABA-T) is the enzyme

that catalyzes the transamination. Pyridoxal phosphate, a de-

rivative of the B complex vitamin pyridoxine, is a cofactor for

GAD and GABA-T. In addition, there is an active reuptake of

GABA via the GABA transporter. A vesicular GABA trans-

porter (VGAT) transports GABA and glycine into secretory

vesicles.

GABA Receptors

Three subtypes of GABA receptors have been identified:

GABAA, GABAB, and GABAC. The GABAA and GABAB re-

ceptors are widely distributed in the CNS, whereas in adult ver-

tebrates the GABAC receptors are found almost exclusively in

the retina. The GABAA and GABAC receptors are ion channels

made up of five subunits surrounding a pore, like the nicotinic

acetylcholine receptors and many of the glutamate receptors. In

this case, the ion is Cl– (Figure 7–10). The GABAB receptors are

metabotropic and are coupled to heterotrimeric G proteins that

increase conductance in K+ channels, inhibit adenylyl cyclase,

and inhibit Ca2+ influx. Increases in Cl– influx and K+ efflux

and decreases in Ca2+ influx all hyperpolarize neurons, produc-

ing an IPSP. The G protein mediation of GABAB receptor ef-

fects is unique in that a G protein heterodimer, rather than a

single protein, is involved.

The GABAC receptors are relatively simple in that they are

pentamers of three ρ subunits in various combinations. On

FIGURE 7–9 Diagrammatic representation of the NMDA

receptor. When glycine and glutamate bind to the receptor, the

closed ion channel (left) opens, but at the resting membrane poten-

tial, the channel is blocked by Mg2+ (right). This block is removed if

partial depolarization is produced by other inputs to the neuron con-

taining the receptor, and Ca2+ and Na+ enter the neuron. Blockade can

also be produced by the drug dizocilpine maleate (MK-801).

L-Glutamate Glycine

Extracellular

Intracellular

Ca^2 + Na+

K+

Closed ion channel Open ion channel

Channel

blocker

Mg^2 +

MK-801