DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

+
–
block axonal conduction; they do so by blocking the
voltage-sensitive Na + channel and preventing the
increase in Na + permeability associated with the rising
phase of the action potential. In contrast, batrachotoxin,
an extremely potent steroidal alkaloid secreted by a
South American frog, produces paralysis through a
selective increase in permeability of the Na + channel,
which induces a persistent depolarization. Scorpion
toxins are peptides that also cause persistent depolarization,
but they do so by inhibiting the inactivation
process (Catterall, 2000). Na + and Ca 2+ channels are
discussed in more detail in Chapters 11, 14, and 20.
Junctional Transmission. The arrival of the action
potential at the axonal terminals initiates a series of
events that trigger transmission of an excitatory or
inhibitory impulse across the synapse or neuroeffector
junction. These events, diagrammed in Figure 8–3, are:
1. Storage and release of the transmitter. The nonpeptide
(small molecule) neurotransmitters are
MEMBRANE
POTENTIAL
(mV)
excitatory
input
Na +
K +
Na + Ca 2+ K +
K +
Cl –
inhibitory
input
MEMBRANE
POTENTIAL
(mV)
+
0
–
1. AP 2. EPSP
+ 1. AP
0
–
–
+
+
–
–
+
+
–
3. AP
2. IPSP 3. Inhibition
+
–
+
–
largely synthesized in the region of the axonal terminals
and stored there in synaptic vesicles.
Peptide neurotransmitters (or precursor peptides)
are found in large dense-core vesicles that are
transported down the axon from their site of synthesis
in the cell body. During the resting state,
there is a continual slow release of isolated quanta
of the transmitter; this produces electrical
responses at the postjunctional membrane [miniature
end-plate potentials (mepps)] that are associated
with the maintenance of physiological
responsiveness of the effector organ. A low level
of spontaneous activity within the motor units of
skeletal muscle is particularly important because
skeletal muscle lacks inherent tone. The action
potential causes the synchronous release of several
hundred quanta of neurotransmitter. Depolarization
of the axonal terminal triggers this process; a critical
step in most nerve endings is the influx of Ca 2+ ,
which enters the axonal cytoplasm and promotes
fusion between the axoplasmic membrane and
synaptic gap
Ca 2+ Na +
voltage-sensitive
Na + channel
Na +
β 1 β 2
DOCKING COMPLEX
neurexin
syntaxin
Rab 3
synaptobrevin
synaptotagmin
neuro-
transmitter
transporter
voltage-sensitive
Ca 2+ channel
postsynaptic
receptor-gated
ion channel
SYNAPTIC VESICLES
excitatory
transmitter
inhibitory
transmitter
Figure 8–3. Steps involved in excitatory and inhibitory neurotransmission. 1. The nerve action potential (AP) consists of a transient selfpropagated
reversal of charge on the axonal membrane. (The internal potential E i
goes from a negative value, through zero potential, to a
slightly positive value primarily through increases in Na + permeability and then returns to resting values by an increase in K + permeability.)
When the AP arrives at the presynaptic terminal, it initiates release of the excitatory or inhibitory transmitter. Depolarization at the nerve
ending and entry of Ca 2+ initiate docking and then fusion of the synaptic vesicle with the membrane of the nerve ending. Docked and fused
vesicles are shown. 2. Combination of the excitatory transmitter with postsynaptic receptors produces a localized depolarization, the excitatory
postsynaptic potential (EPSP), through an increase in permeability to cations, most notably Na + . The inhibitory transmitter causes
a selective increase in permeability to K + or Cl – , resulting in a localized hyperpolarization, the inhibitory postsynaptic potential (IPSP).
3. The EPSP initiates a conducted AP in the postsynaptic neuron; this can be prevented, however, by the hyperpolarization induced by a
concurrent IPSP. The transmitter is dissipated by enzymatic destruction, by reuptake into the presynaptic terminal or adjacent glial cells,
or by diffusion. Depolarization of the postsynaptic membrane can permit Ca 2+ entry if voltage-gated Ca 2+ channels are present. (Reproduced
with permission from Brunton L, Parker K, Blumenthal D, Buxton I (eds). Goodman & Gilman’s Manual of Pharmacology and
Therapeutics. New York: McGraw-Hill, 2008, p 94. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)
α
183
CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS