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

184 those vesicles in close proximity to it (Meir et al.,
1999). The contents of the vesicles, including
enzymes and other proteins, then are discharged to
the exterior by a process termed exocytosis.
Synaptic vesicles may either fully exocytose with
complete fusion and subsequent endocytosis or
form a transient pore that closes after transmitter
has escaped (Murthy and Stevens, 1998).
SECTION II
NEUROPHARMACOLOGY
Synaptic vesicles are clustered in discrete areas underlying
the presynaptic plasma membrane, termed active zones; they often
are aligned with the tips of postsynaptic folds. Some 20-40 proteins,
playing distinct roles as transporter or trafficking proteins, are found
in the vesicle. Neurotransmitter transport into the vesicle is driven
by an electrochemical gradient generated by the vacuolar proton
pump.
The vesicle protein synaptobrevin (VAMP) assembles with
the plasma membrane proteins SNAP-25 and syntaxin 1 to form a
core complex that initiates or drives the vesicle–plasma membrane
fusion process (Jahn et al., 2003). The submillisecond triggering of
exocytosis by Ca 2+ appears to be mediated by a separate family of
proteins, the synaptotagmins. GTP-binding proteins of the Rab 3
family regulate the fusion. Several other regulatory proteins of less
well-defined function—synapsin, synaptophysin, and synaptogyrin—also
play a role in fusion and exocytosis, as do proteins such
as RIM and neurexin that are found on the active zones of the plasma
membrane. Many of the trafficking proteins are homologous to those
used in vesicular transport in yeast.
An extensive variety of receptors has been identified on soma,
dendrites, and axons of neurons, where they respond to neurotransmitters
or modulators released from the same neuron or from adjacent
neurons or cells (Miller, 1998; Westfall, 2004). Soma–dendritic
receptors are those receptors located on or near the cell body and
dendrites; when activated, they primarily modify functions of the
soma–dendritic region such as protein synthesis and generation of
action potentials. Presynaptic receptors are those presumed to be
located on, in, or near axon terminals or varicosities; when activated,
they modify functions of the terminal region such as synthesis and
release of transmitters. Two main classes of presynaptic receptors
have been identified on most neurons, including sympathetic and
parasympathetic terminals. Heteroreceptors are presynaptic receptors
that respond to neurotransmitters, neuromodulators, or neurohormones
released from adjacent neurons or cells. For example, NE
can influence the release of ACh from parasympathetic neurons by
acting on α 2A
, α 2B
, and α 2C
receptors, whereas ACh can influence the
release of NE from sympathetic neurons by acting on M 2
and M 4
receptors (described later in the chapter). The other class of presynaptic
receptors consists of autoreceptors, which are receptors
located on or close to those axon terminals of a neuron through
which the neuron’s own transmitter can modify transmitter synthesis
and release. For example, NE released from sympathetic neurons
may interact with α 2A
and α 2C
receptors to inhibit neurally released
NE. Similarly, ACh released from parasympathetic neurons may
interact with M 2
and M 4
receptors to inhibit neurally released ACh.
Presynaptic nicotinic receptors enhance transmitter release
in motor neurons (Bowman et al., 1990) and in a variety of other
central and peripheral synapses (MacDermott et al., 1999).
Adenosine, dopamine (DA), glutamate, γ-aminobutyric acid
(GABA), prostaglandins, and enkephalins have been shown to influence
neurally mediated release of various neurotransmitters. The
receptors for these agents exert their modulatory effects in part by
altering the function of prejunctional ion channels (Miller, 1998; Tsien
et al., 1988). A number of ion channels that directly control transmitter
release are found in presynaptic terminals (Meir et al., 1999).
2. Combination of the transmitter with postjunctional
receptors and production of the postjunctional
potential. The transmitter diffuses across the
synaptic or junctional cleft and combines with specialized
receptors on the postjunctional membrane;
this often results in a localized increase in the ionic
permeability, or conductance, of the membrane.
With certain exceptions (noted in the following discussion),
one of three types of permeability change
can occur:
• a generalized increase in the permeability to
cations (notably Na + but occasionally Ca 2+ ),
resulting in a localized depolarization of the
membrane, that is, an excitatory postsynaptic
potential (EPSP)
• a selective increase in permeability to anions,
usually Cl – , resulting in stabilization or actual
hyperpolarization of the membrane, which
constitutes an inhibitory postsynaptic potential
(IPSP)
• an increased permeability to K + . Because the
K + gradient is directed out of the cell, hyperpolarization
and stabilization of the membrane
potential occur (an IPSP)
The potential changes associated with the EPSP and IPSP at
most sites are the results of passive fluxes of ions down their concentration
gradients. The changes in channel permeability that cause
these potential changes are specifically regulated by the specialized
postjunctional receptors for the neurotransmitter that initiates the
response (see Figures 8–4, 8–5 11–5, and Chapter 14). These receptors
may be clustered on the effector cell surface, as seen at the neuromuscular
junctions of skeletal muscle and other discrete synapses,
or distributed more uniformly, as observed in smooth muscle.
By using microelectrodes that form high-resistance seals on
the surface of cells, electrical events associated with a single neurotransmitter-gated
channel can be recorded (Hille, 1992). In the
presence of an appropriate neurotransmitter, the channel opens rapidly
to a high-conductance state, remains open for about a millisecond,
and then closes. A short square-wave pulse of current is
observed as a result of the channel’s opening and closing. The summation
of these microscopic events gives rise to the EPSP. The
graded response to a neurotransmitter usually is related to the frequency
of opening events rather than to the extent of opening or the
duration of opening. High-conductance ligand-gated ion channels
usually permit passage of Na + or Cl – ; K + and Ca 2+ are involved less