1.

Amino Acids as Neurotransmitters

Excitatory Neurotransmitters

The amino acids glutamic acid and, to a lesser degree, aspartic acid, function as excitatory
neurotransmitters in the CNS. Glutamic acid (or glutamate), indeed, is the major excitatory
neurotransmitter in the brain, produc- ing excitatory postsynaptic potentials (EPSPs) in at least 80% of
the synapses in the cerebral cortex. The energy consumed by active transport carriers needed to
maintain the ionic gradients for these EPSPs constitutes the major energy requirement of the brain
(action potentials pro- duced by axons are more energy efficient than EPSPs). Astrocytes take
glutamate from the synaptic cleft, as pre- viously described, and couple this to increased glucose uptake
and increased blood flow via vasodilation to the more active brain regions.

Research has revealed that each of the glutamate recep- tors encloses an ion channel, similar to the arrangement
seen in the nicotinic ACh receptors (see fig. 7.26). Among these EPSP-producing glutamate receptors, three
subtypes can be distinguished. These are named according to the molecules (other than glutamate) that they
bind: (1) NMDA receptors (named for N-methyl-D-aspartate); (2)AMPA receptors; and (3) kainate
receptors. NMDA and AMPA receptors are illustrated in chapter 8, figure 8.16.

The NMDA receptors for glutamate are involved in mem- ory storage, as will be discussed in section 7.7 and
chapter 8, section 8.2. These receptors are quite complex because the ion channel will not open simply by the
binding of glutamate to its receptor. Instead, two other conditions must be met at the same time: (1) the NMDA
receptor must also bind to glycine (or D-serine, which has recently been shown to be produced by astrocytes);
and (2) the membrane must be par- tially depolarized at this time by a different neurotransmit- ter molecule that
binds to a different receptor (for example, by glutamate binding to the AMPA receptors, as shown in fig. 8.16).
Depolarization causes Mg2+ to be released from the NMDA channel pore, unblocking the channel and allow- ing
the entry of Ca2+ and Na+ (and exit of K+) through NMDA channels in the dendrites of the postsynaptic neuron.

Inhibitory Neurotransmitters

The amino acid glycine is inhibitory; instead of depolarizing the postsynaptic membrane and producing an
EPSP, it hyper- polarizes the postsynaptic membrane and produces an inhibi- tory postsynaptic potential (IPSP).
The binding of glycine to its receptor proteins causes the opening of chloride (Cl−) channels in the postsynaptic
membrane (fig. 7.32). As a result, Cl− dif- fuses into the postsynaptic membrane as long as the mem- brane
potential is less negative (more depolarized) than the chloride equilibrium potential (chapter 6). This may not be
the case at rest, because the chloride equilibrium potential may be close to the resting membrane potential.
However, if an excit- atory neurotransmitter partially depolarizes the membrane, the movement of Cl − through
its open channels is promoted. When this occurs, the hyperpolarizing effects of Cl− entering the cell make it
more difficult for the postsynaptic neuron to reach the threshold depolarization required to stimulate action
potentials. Thus, the opening of Cl− channels by an inhibitory neurotransmitter renders excitatory input less
effective.

The inhibitory effects of glycine are very important in the spinal cord, where they help in the control of skeletal
move- ments (chapter 12; see figs. 12.30 and 12.31). Flexion of an arm, for example, involves stimulation of the
flexor muscles by motor neurons in the spinal cord. The motor neurons that innervate the antagonistic extensor
muscles are inhibited by IPSPs produced by glycine released from other neurons. The importance of the
inhibitory actions of glycine is revealed by the deadly effects of strychnine, a poison that causes spastic
paralysis by specifically blocking the glycine receptor pro- teins. Animals poisoned with strychnine die from
asphyxia- tion because they are unable to relax the diaphragm.

The neurotransmitter gamma-aminobutyric acid (GABA) is a derivative of another amino acid, glutamic acid.
GABA is the most prevalent neurotransmitter in the brain; in fact, as many as one-third of all the neurons in the
brain use GABA as a neu- rotransmitter. Like glycine, GABA is inhibitory—it hyperpolarizes

the postsynaptic membrane by opening Cl− channels. Also, the effects of GABA, like those of glycine, are
involved in motor control. For example, the large Purkinje cells mediate the motor functions of the cerebellum
by producing IPSPs in their post- synaptic neurons. A deficiency of GABA-releasing neurons is responsible for
the uncontrolled movements seen in people with Huntington’s disease. Huntington’s disease is a neuro-
degenerative disorder caused by a defect in the huntingtin gene (chapter 3, section 3.4).