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

some smooth muscles when the membrane has been depolarized
completely by high concentrations of K + , provided that Ca 2+ is present.
Hence, ACh stimulates ion fluxes across membranes and/or
mobilizes intracellular Ca 2+ to cause contraction.
In the heart, spontaneous depolarizations normally arise from
the SA node. In the cardiac conduction system, particularly in the SA
and AV nodes, stimulation of the cholinergic innervation or the
direct application of ACh causes inhibition, associated with hyperpolarization
of the membrane and a marked decrease in the rate of
depolarization. These effects are due, at least in part, to a selective
increase in permeability to K + (Hille, 1992).
Autonomic Ganglia. The primary pathway of cholinergic transmission
in autonomic ganglia is similar to that at the neuromuscular
junction of skeletal muscle. Ganglion cells can be discharged by
injecting very small amounts of ACh into the ganglion. The initial
depolarization is the result of activation of nicotinic ACh receptors,
which are ligand-gated cation channels with properties similar to
those found at the neuromuscular junction. Several secondary transmitters
or modulators either enhance or diminish the sensitivity of
the postganglionic cell to ACh. This sensitivity appears to be related
to the membrane potential of the postsynaptic nerve cell body or its
dendritic branches. Ganglionic transmission is discussed in more
detail in Chapter 11.
Prejunctional Sites. As described earlier, both cholinergic and adrenergic
nerve terminal varicosities contain autoreceptors and heteroreceptors.
ACh release therefore is subject to complex regulation by
mediators, including ACh itself acting on M 2
and M 4
autoreceptors,
and other transmitters (e.g., NE acting on α 2A
and α 2C
adrenergic
receptors) (Philipp and Hein, 2004; Wess, 2004) or substances
produced locally in tissues (e.g., NO). ACh-mediated inhibition of
ACh release following activation of M 2
and M 4
autoreceptors is
thought to represent a physiological negative-feedback control mechanism.
At some neuroeffector junctions such as the myenteric plexus
in the GI tract or the SA node in the heart, sympathetic and parasympathetic
nerve terminals often lie juxtaposed to each other. The
opposing effects of norepinephrine and ACh, therefore, result not
only from the opposite effects of the two transmitters on the smooth
muscle or cardiac cells but also from the inhibition of ACh release
by NE or inhibition of NE release by ACh acting on heteroreceptors
on parasympathetic or sympathetic terminals. The muscarinic
autoreceptors and heteroreceptors also represent drug targets for both
agonists and antagonists. Muscarinic agonists can inhibit the electrically
induced release of ACh, whereas antagonists will enhance the
evoked release of transmitter. The parasympathetic nerve terminal
varicosities also may contain additional heteroreceptors that could
respond by inhibition or enhancement of ACh release by locally
formed autacoids, hormones, or administered drugs. In addition to
α 2A
and α 2C
adrenergic receptors, other inhibitory heteroreceptors
on parasympathetic terminals include adenosine A 1
receptors, histamine
H 3
receptors, and opioid receptors. Evidence also exists for
β 2
-adrenergic facilitatory receptors.
Extraneuronal Sites. A large body of evidence now indicates that all
elements of the cholinergic system including the enzyme ChAT, ACh
synthesis, ACh release mechanisms, and both mAChRs and
nAChRs, are functionally expressed independently of cholinergic
innervation in numerous non-neuronal cells including those of
humans. These non-neuronal cholinergic systems can both modify
and control phenotypic cell functions such as proliferation,
differentiation, formation of physical barriers, migration, and ion
and water movements. The widespread synthesis of ACh in nonneuronal
cells has changed the thinking that ACh acts only as a neurotransmitter.
Each component of the cholinergic system in
non-neuronal cells can be affected by pathophysiological conditions
or secondary to disease states. For instance, blockade of mAChRs
and nAChRs on non-neuronal cells can cause cellular dysfunction
and cell death. Moreover, dysfunctions of non-neuronal cholinergic
systems may be involved in the pathogenesis of diseases (e.g.,
inflammatory processes) (Kalamida et al., 2007; Wessler and
Kirkpatrick, 2008).
Cholinergic Receptors and Signal
Transduction
Sir Henry Dale noted that the various esters of choline
elicited responses that were similar to those of either
nicotine or muscarine depending on the pharmacological
preparation. A similarity in response also was noted
between muscarine and nerve stimulation in those
organs innervated by the craniosacral divisions of the
autonomic nervous system. Thus, Dale suggested that
ACh or another ester of choline was a neurotransmitter
in the autonomic nervous system; he also stated that
the compound had dual actions, which he termed a
“nicotine action” (nicotinic) and a “muscarine action”
(muscarinic).
The capacities of tubocurarine and atropine to block nicotinic
and muscarinic effects of ACh, respectively, provided further support
for the proposal of two distinct types of cholinergic receptors.
Although Dale had access only to crude plant alkaloids of then
unknown structure from Amanita muscaria and Nicotiana tabacum,
this classification remains as the primary subdivision of cholinergic
receptors. Its utility has survived the discovery of several distinct
subtypes of nicotinic and muscarinic receptors.
Although ACh and certain other compounds stimulate both
muscarinic and nicotinic cholinergic receptors, several other agonists
and antagonists are selective for one of the two major types of
receptors. ACh is a flexible molecule, and indirect evidence suggests
that the conformations of the neurotransmitter are distinct when it is
bound to nicotinic or muscarinic cholinergic receptors.
Nicotinic receptors are ligand-gated ion channels whose activation
always causes a rapid (millisecond) increase in cellular permeability
to Na + and Ca 2+ , depolarization, and excitation. By
contrast, muscarinic receptors are G protein–coupled receptors
(GPCRs). Responses to muscarinic agonists are slower; they may be
either excitatory or inhibitory, and they are not necessarily linked to
changes in ion permeability.
The primary structures of various species of nicotinic receptors
(Changeux and Edelstein, 1998; Numa et al., 1983) and muscarinic
receptors (Bonner, 1989; Caulfield and Birdsall, 1998) have
been deduced from the sequences of their respective genes. That
these two types of receptors belong to distinct families of proteins is
not surprising, retrospectively, in view of their distinct differences in
chemical specificity and function.
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CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS