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

frequently. The preceding ligand-gated channels belong to a large
superfamily of ionotropic receptor proteins that includes the nicotinic,
glutamate, and certain serotonin (5-HT 3
) and purine receptors,
which conduct primarily Na + , cause depolarization, and are excitatory;
and GABA and glycine receptors, which conduct Cl – , cause
hyperpolarization, and are inhibitory. The nicotinic, GABA, glycine,
and 5-HT 3
receptors are closely related, whereas the glutamate and
purinergic ionotropic receptors have distinct structures (Karlin and
Akabas, 1995). Neurotransmitters also can modulate the permeability
of K + and Ca 2+ channels indirectly. In these cases, the receptor
and channel are separate proteins, and information is conveyed
between them by G proteins. Other receptors for neurotransmitters
act by influencing the synthesis of intracellular second messengers
and do not necessarily cause a change in membrane potential. The
most widely documented examples of receptor regulation of secondmessenger
systems are the activation or inhibition of adenylyl cyclase
to modulate cellular cyclic AMP concentrations and the increase in
cytosolic concentrations of Ca 2+ that results from release of the ion
from internal stores by inositol trisphosphate (see Chapter 3).
3. Initiation of postjunctional activity. If an EPSP
exceeds a certain threshold value, it initiates a propagated
action potential in a postsynaptic neuron or
a muscle action potential in skeletal or cardiac
muscle by activating voltage-sensitive channels in
the immediate vicinity. In certain smooth muscle
types in which propagated impulses are minimal,
an EPSP may increase the rate of spontaneous
depolarization, cause Ca 2+ release, and enhance
muscle tone; in gland cells, the EPSP initiates
secretion through Ca 2+ mobilization. An IPSP,
which is found in neurons and smooth muscle but
not in skeletal muscle, will tend to oppose excitatory
potentials simultaneously initiated by other
neuronal sources. Whether a propagated impulse
or other response ensues depends on the summation
of all the potentials.
4. Destruction or dissipation of the transmitter.
When impulses can be transmitted across junctions
at frequencies up to several hundred per second,
there must be an efficient means of disposing
of the transmitter following each impulse. At
cholinergic synapses involved in rapid neurotransmission,
high and localized concentrations of
acetylcholinesterase (AChE) are available for this
purpose. When AChE activity is inhibited, removal
of the transmitter is accomplished principally by
diffusion. Under these circumstances, the effects
of released ACh are potentiated and prolonged (see
Chapter 10).
Rapid termination of NE occurs by a combination
of simple diffusion and reuptake by the axonal
terminals of most of the released norepinephrine.
Termination of the action of amino acid transmitters
results from their active transport into neurons
and surrounding glia. Peptide neurotransmitters are
hydrolyzed by various peptidases and dissipated by
diffusion; specific uptake mechanisms have not
been demonstrated for these substances.
5. Non-electrogenic functions. The continual quantal
release of neurotransmitters in amounts insufficient
to elicit a postjunctional response probably is
important in the transjunctional control of neurotransmitter
action. The activity and turnover of
enzymes involved in the synthesis and inactivation
of neurotransmitters, the density of presynaptic and
postsynaptic receptors, and other characteristics of
synapses probably are controlled by trophic actions
of neurotransmitters or other trophic factors
released by the neuron or the target cells (Sanes
and Lichtman, 1999).
Cholinergic Transmission
The synthesis, storage, and release of ACh follow a similar
life cycle in all cholinergic synapses, including
those at skeletal neuromuscular junctions, preganglionic
sympathetic and parasympathetic terminals,
postganglionic parasympathetic varicosities, postganglionic
sympathetic varicosities innervating sweat glands in the
skin, and in the CNS. The neurochemical events that
underlie cholinergic neurotransmission are summarized
in Figure 8–4. Two enzymes, choline acetyltransferase
and AChE, are involved in ACh synthesis and degradation,
respectively.
Choline Acetyltransferase. Choline acetyltransferase
catalyzes the final step in the synthesis of ACh—the
acetylation of choline with acetyl coenzyme A (CoA)
(Wu and Hersh, 1994). The primary structure of choline
acetyltransferase is known from molecular cloning, and
its immunocytochemical localization has proven useful
for identification of cholinergic axons and nerve cell
bodies.
Acetyl CoA for this reaction is derived from pyruvate via the
multistep pyruvate dehydrogenase reaction or is synthesized by
acetate thiokinase, which catalyzes the reaction of acetate with ATP
to form an enzyme-bound acyladenylate (acetyl AMP). In the presence
of CoA, transacetylation and synthesis of acetyl CoA proceed.
Choline acetyltransferase, like other protein constituents of
the neuron, is synthesized within the perikaryon and then is transported
along the length of the axon to its terminal. Axonal terminals
contain a large number of mitochondria, where acetyl CoA is synthesized.
Choline is taken up from the extracellular fluid into the
axoplasm by active transport. The final step in the synthesis occurs
within the cytoplasm, following which most of the ACh is
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CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS