The Nervous System 183and forms a complex with a larger protein molecule (the recep-
tor). Binding of the neurotransmitter ligand to its receptor pro-
tein causes ion channels to open in the postsynaptic membrane.
The gates that regulate these channels, therefore, can be called
chemically regulated (or ligand-regulated ) gates because
they open in response to the binding of a chemical ligand to its
receptor in the postsynaptic plasma membrane.
Note that two broad categories of gated ion channels have
been described: voltage-regulated and chemically regulated.
Voltage-regulated channels are found primarily in the axons;
chemically regulated channels are found in the postsynaptic
membrane. Voltage-regulated channels open in response to
depolarization; chemically regulated channels open in response
to the binding of postsynaptic receptor proteins to their neu-
rotransmitter ligands.
When the chemically regulated ion channels are opened,
they produce a graded change in the membrane potential,
also known as a graded potential. The opening of specific
channels—particularly those that allow Na^1 or Ca^2 1 to enter
the cell—produces a graded depolarization, where the inside
of the postsynaptic membrane becomes less negative. This
depolarization is called an excitatory postsynaptic potential
(EPSP) because the membrane potential moves toward the
threshold required for action potentials. In other cases, as when
CI^2 enters the cell through specific channels, a graded hyper-
polarization is produced (where the inside of the postsynaptic
membrane becomes more negative). This hyperpolarization is
called an inhibitory postsynaptic potential (IPSP) because
the membrane potential moves farther from the threshold depo-
larization required to produce action potentials. The mecha-
nisms by which specific neurotransmitters produce graded
EPSPs and IPSPs will be described in the sections that follow.
Excitatory postsynaptic potentials, as their name implies,
stimulate the postsynaptic cell to produce action potentials,
and inhibitory postsynaptic potentials antagonize this effect. In
synapses between the axon of one neuron and the dendrites of
another, the EPSPs and IPSPs are produced at the dendrites
and must propagate to the initial segment of the axon to influ-
ence action potential production ( fig. 7.24 ).
Synaptic potentials (EPSPs and IPSPs) decrease in ampli-
tude as they are conducted along the dendrites and cell body to
the axon hillock. Adjacent to the axon hillock, and comprising
5 to 80 m m of unmyelinated axon from the cell body to the first
myelin sheath (of myelinated axons), is the axon initial segment.
This has a high density of Na^1 and K^1 channels and is the region
where the action potential is first produced. It serves as the site
where much synaptic integration occurs, including the summa-
tion of EPSPs and IPSPs (section 7.7). Once action potentials are
produced at the initial segment, they will regenerate themselves
along the axon as previously described. These events are illus-
trated in figure 7.24 and summarized in figure 7.25. Addition-
ally, in neurons of the cerebral cortex, action potentials have been
shown to “back propagate” from the axon initial segment to the
dendrites. This is believed to aid the synaptic events involved in
learning and memory (section 7.7).action potentials at the axon terminal, there is a greater entry of
Ca^2 1 , and thus a larger number of synaptic vesicles undergoing
exocytosis and releasing neurotransmitter molecules. As a result,
a greater frequency of action potentials by the presynaptic axon
will result in greater stimulation of the postsynaptic neuron.
Before an action potential arrives at the axon terminal,
many synaptic vesicles are already attached, or docked, to spe-
cialized sites of the presynaptic plasma membrane. Docking
involves a SNARE complex of proteins that bridge the vesicle
membrane and the plasma membrane. The SNARE proteins
include one in the vesicle membrane ( synaptobrevin-2 ) and two
anchored in the plasma membrane ( syntaxin and SNAP - 25 ).
When an action potential arrives at the presynaptic axon termi-
nal, depolarization opens Ca^2 1 channels in the plasma mem-
brane. Ca^2 1 enters the cytoplasm and binds to a Ca^2 1 sensor
protein, termed synaptotagmin, anchored to the synaptic ves-
icle membrane. Through a mechanism not fully understood,
this interacts with the SNARE complex and leads in less than
a millisecond to fusion of the vesicle and plasma membrane,
the formation of a pore, and the exocytosis of neurotransmitter.
The scientists who discovered how synaptic vesicles dock and
release their neurotransmitters were awarded the 2013 Nobel
Prize in Physiology or Medicine.
CLINICAL APPLICATION
Tetanus toxin and botulinum toxin ( Botox ) are potentially
deadly bacterial products that block the release of neuro-
transmitters. These neurotoxins are proteases (enzymes
that digest proteins) that destroy specific proteins of the
SNARE complex, thereby inhibiting exocytosis of neu-
rotransmitters. Tetanus toxin targets inhibitory synapses—
those that release glycine or GABA as neurotransmitters
(see section 7.6) and digests synaptobrevin-2. Through this
action, tetanus toxin causes muscle rigidity (leading to the
name lockjaw ) and spastic paralysis. Botulinum toxin targets
excitatory synapses that release ACh as a neurotransmitter
and digests SNAP-25. As a result, botulinum toxin produces
flaccid paralysis, where the muscles are unable to contract.
Small amounts of this toxin delivered as Botox injections
are used cosmetically to smooth wrinkles.Actions of Neurotransmitter
Once the neurotransmitter molecules have been released from
the presynaptic axon terminals, they diffuse rapidly across the
synaptic cleft and reach the membrane of the postsynaptic cell.
The neurotransmitters then bind to specific receptor proteins
that are part of the postsynaptic membrane. Receptor proteins
have high specificity for their neurotransmitter, which is the
ligand of the receptor protein. The term ligand in this case
refers to a smaller molecule (the neurotransmitter) that binds to