170
Chapter 6
drive it out of the way the membrane must be signifi cantly depo-
larized by the current through AMPA channels (step 5). This
explains why it requires a high frequency of presynaptic action
potentials to complete the long-term potentiation mechanism:
At low frequencies there is insuffi cient temporal summation of
AMPA-receptor EPSPs to provide the 20–30 mV of depolariza-
tion needed to move the magnesium ion, and so the NMDA
receptors do not open. When the depolarization is suffi cient,
however, NMDA receptors do open, allowing calcium to enter
the postsynaptic cell (step 6). Calcium then activates a second-
messenger cascade in the postsynaptic cell that includes persistent
activation of two different protein kinases, and which increases
the sensitivity of the postsynaptic neuron to glutamate (step
7). This second-messenger system can also activate long-term
enhancement of presynaptic glutamate release via a retrograde
messenger not yet identifi ed (step 8). Each subsequent action
potential arriving along this presynaptic cell will cause a greater
depolarization of the postsynaptic membrane. Thus, repeatedly
and intensely activating a particular pattern of synaptic fi ring
(as you might when studying for an exam) causes chemical and
structural changes that facilitate future activity along those same
pathways (as might occur when recalling what you learned).
NMDA receptors have also been implicated in medi-
ating
excitotoxicity.
This is a phenomenon in which the
injury or death of some brain cells (due, for example, to
blocked or ruptured blood vessels) rapidly spreads to adja-
cent regions. When glutamate-containing cells die and their
membranes rupture, the fl ood of glutamate excessively stim-
ulates AMPA and NMDA receptors on nearby neurons. The
excessive stimulation of those neurons causes the accumula-
tion of toxic levels of intracellular calcium, which in turn
kills those neurons and causes
them
to rupture, and the
wave of damage progressively spreads. Recent experiments
and clinical trials suggest that administering NMDA recep-
tor antagonists may help minimize the spread of cell death
following injuries to the brain.
GABA
GABA (gamma-aminobutyric acid)
is the major inhibitory
neurotransmitter in the brain. Although it is not one of the
20 amino acids used to build proteins, it is classifi
ed with the
amino acid neurotransmitters because it is a modifi ed form of
glutamate. With few exceptions, GABA neurons in the brain are
small interneurons that dampen activity within neural circuits.
Postsynaptically, GABA may bind to ionotropic or metabo-
tropic receptors. The ionotropic receptor increases chloride fl
ux
into the cell, resulting in hyperpolarization of the postsynaptic
membrane. In addition to the GABA binding site, this recep-
tor has several additional binding sites for other compounds,
including steroids, barbiturates, ethanol, and benzodiazepines.
Benzodiazepine drugs such as
Xanax
®
and
Valium
®
reduce
anxiety, guard against seizures, and induce sleep, by increasing
chloride fl ux through the GABA receptor.
Glycine
Glycine
is the major neurotransmitter released from inhibi-
tory interneurons in the spinal cord and brainstem. It binds
to ionotropic receptors on postsynaptic cells that allow chlo-
ride to enter, thus hyperpolarizing or stabilizing the resting
membrane potential. Normal function of glycinergic neurons
is essential for maintaining a balance of excitatory and inhibi-
tory activity in spinal cord integrating centers that regulate
skeletal muscle contraction. This becomes apparent in cases
of poisoning with the neurotoxin
strychnine,
an antago-
nist of glycine receptors. Victims experience hyperexcitability
throughout the nervous system, which leads to convulsions,
spastic contraction of skeletal muscles, and ultimately death
due to impairment of the muscles of respiration.
Neuropeptides
The
neuropeptides
are composed of two or more amino
acids linked together by peptide bonds. Some 85 neuropep-
tides have been identifi ed, but their physiological roles are
often unknown. It seems that evolution has selected the same
chemical messengers for use in widely differing circumstances,
and many of the neuropeptides had been previously identifi ed
in nonneural tissue where they function as hormones or para-
crine agents. They generally retain the name they were given
when fi rst discovered in the nonneural tissue.
The neuropeptides are formed differently from other
neurotransmitters, which are synthesized in the axon termi-
nals by very few enzyme-mediated steps. The neuropeptides,
in contrast, are derived from large precursor proteins, which
in themselves have little, if any, inherent biological activ-
ity. The synthesis of these precursors, directed by mRNA,
occurs on ribosomes, which exist only in the cell body and
large dendrites of the neuron, often a considerable distance
from axon terminals or varicosities where the peptides are
released.
In the cell body, the precursor protein is packaged into
vesicles, which are then moved by axonal transport into the
terminals or varicosities, where the protein is cleaved by spe-
cifi c peptidases. Many of the precursor proteins contain mul-
tiple peptides, which may be different or be copies of one
peptide. Neurons that release one or more of the peptide neu-
rotransmitters are collectively called
peptidergic.
In many
cases, neuropeptides are cosecreted with another type of neu-
rotransmitter and act as neuromodulators.
The amount of peptide released from vesicles at synapses
is signifi
cantly lower than the amount of nonpeptidergic neu-
rotransmitters such as catecholamines. In addition, neuro-
peptides can diffuse away from the synapse and affect other
neurons at some distance, in which case they are referred to as
neuromodulators. The actions of these neuromodulators are
longer-lasting (on the order of several hundred milliseconds)
than when peptides or other molecules act as neurotransmit-
ters. After release, peptides can interact with either ionotropic
or metabotropic receptors. They are eventually broken down
by peptidases located in the neuronal membrane.
Endogenous opioids,
a group of neuropeptides that
includes
beta-endorphin,
the
dynorphins,
and the
enkeph-
alins
—have attracted much interest because their recep-
tors are the sites of action of opiate drugs such as
morphine
and
codeine.
The opiate drugs are powerful
analgesics
(that
is, they relieve pain without loss of consciousness), and the
endogenous opioids undoubtedly play a role in regulating
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