Prejunctional Receptors
Acetylcholine receptors exist as a variety of forms separate from
that seen in muscle.[79]
These receptors are expressed
in peripheral neurons, autonomic and sensory
ganglia, and in the central nervous system. There is also direct and indirect evidence
for their existence in lymphocytes, fibroblasts, chondrocytes, macrophages, and granulocytes.
Sixteen acetylcholine subunit genes have been cloned from vertebrates. They include
various combinations of α-subunits (α1
through α9
)
and β-subunits (β1
through β4
) and one each
of γ-, δ-, and epsilon-subunits.
Prejunctional- or nerve terminal-associated cholinergic receptors
have been demonstrated pharmacologically and by molecular biology techniques, but
their form and functions are not well understood compared with those in the postjunctional
area. Many drugs with an abundance of potential targets for drug action can affect
the capacity of the nerve terminal to carry out its functions. The trophic function
to maintain the nerve-muscle contact involves release and replenishment of acetylcholine
together with trophic factors that require signaling through many receptors, of which
the prejunctional nicotinic receptor is just one. Succinylcholine produces fasciculations
that can be prevented by nondepolarizing relaxants. Because a fasciculation is,
by definition, the simultaneous contraction of the multitude of muscle cells in a
single motor unit and because only the nerve can synchronize all the muscles in its
motor unit, it became apparent that succinylcholine must also act on nerve endings.
Because nondepolarizing relaxants prevent fasciculation, it was concluded that they
acted on the same prejunctional receptor. Since then, it has been shown many times
that very small doses of cholinergic agonists (e.g., succinylcholine) and antagonists
(e.g., curare) affect nicotinic receptors on the nerve ending, the former by depolarizing
the ending and sometimes inducing repetitive firing of the nerve and the latter by
preventing the action of agonists.[5]
Another clue to differences between prejunctional and postjunctional
acetylcholine receptors was the finding that although both receptors can bind α-bungarotoxin,
prejunctional binding was reversible, whereas postjunctional binding was not. Additional
clues were found in the many demonstrations of quantitative differences in the reaction
of prejunctional and postjunctional nicotinic receptors to cholinergic agonists and
antagonists.[79]
[80]
For instance, it was known that tubocurarine binds very poorly to the recognition
sites of ganglionic nicotinic cholinoceptors and is not a competitive antagonist
of acetylcholine at this site. Decamethonium is a selective inhibitor of the muscle
receptor, and hexamethonium is a selective inhibitor of the nicotinic receptors in
the autonomic ganglia.[79]
Instead, D-tubocurarine
and hexamethonium can block the opened channels of these receptors and owe their
ability to block ganglionic transmission to this property. The functional characteristics
of the prejunctional receptor channels may also be different. For example, the depolarization
of motor nerve endings initiated by administration of acetylcholine can be prevented
by tetrodotoxin, a specific blocker of sodium flux with no effect on the end plate.
Specific information on the molecular organization of the neuronal
nicotinic receptors on motor neuron terminal is lacking, but work on other parts
of the nervous system such as the brain and ganglia indicate that they are structurally
quite different from those found on the postjunctional muscle membrane.[79]
[80]
Some of the subunit composition is similar,
but other subunits do not resemble that of the postjunctional receptor. Of the 16
different nicotinic acetylcholine receptors gene product identified, only 11 (α2
to α9
and β2
to β4
) are thought
to contribute nicotinic receptors expressed in neurons. Most strikingly, nervous
tissue does not contain genes for γ-, δ-, or epsilon-receptor subunits;
it contains only the genes for the α- and β-subunits. The α- and
β-subunit genes in nerve and muscle are not exactly the same; they are variants.
Muscle contains only one gene for each of the subunits, which are called α1
and α1
-subunit. In contrast, nervous tissue contains neither of
these, but rather contains a number of related genes designated α2
through α9
. To emphasize the distinction between neural and muscle
nicotinic receptors, the former sometimes are designated Nn
and the latter Nm. With so many different subunits
available, there are many possible combinations, and it is not known which combinations
are found in motor nerves. Their physiologic roles have also not been completely
characterized. Expression of neuronal nicotinic acetylcholine receptors in vitro
systems has confirmed that muscle relaxants and their metabolites can bind to these
receptors.[81]
Whether adverse effects observed
during prolonged administration of relaxants could be attributed to interaction of
relaxant with neuronal acetylcholine receptors is unclear.
The nicotinic receptor in the nerve ending of the neuromuscular
junction may serve the function of regulator of transmitter release, as shown in
other parts of the nervous system. The nicotinic receptor on the junctional surface
of the nerve senses transmitter in the cleft and, by means of a positive-feedback
system, causes the release of more transmitter. In other parts of the nervous system,
this positive feedback is complemented by a negative-feedback system, which senses
when the concentration of transmitter in the synaptic cleft has increased appropriately
and shuts down the release system. Indirect evidence suggests that these receptors
are muscarinic cholinergic receptors. Convincing data that motor nerve endings contain
muscarinic receptors or a negative feedback system are not available for the motor
neuron. The nerve ending is also known to bear several other receptors, such as
opioid, adrenergic, dopamine, purine, and adenosine receptors and receptors for endogenous
hormones, neuropeptides, and a variety of proteins. The physiologic roles of these
receptors or the effects of anesthetics on them are unknown.
The motor nerves take up choline, synthesize acetylcholine, store
it in vesicles, and move the vesicles into position to be released by a nerve action
potential, a series of processes known collectively as mobilization.
Muscle relaxants to a greater or lesser extent seem to influence this mobilization
process by acting on the prejunctional nicotinic acetylcholine receptor. Tubocurarine
and related muscle relaxants have a profound effect in decreasing the nerve's capacity
to prepare more acetylcholine for release. Tubocurarine has no direct effect on
the release process for acetylcholine; the amount of transmitter released is controlled
by the availability of releasable acetylcholine and the amount of calcium that enters
the nerve. Although it has frequently been observed
that nondepolarizing relaxants do not diminish the transmitter released by a single
nerve impulse or the first in a high-frequency train of impulses, they sharply decrease
the release triggered by subsequent nerve pulses in the train. The most common manifestation
of this is the so-called tetanic fade commonly seen after a nondepolarizing relaxant
is administered. This effect is thought to result from inhibition of the process
that replenishes releasable acetylcholine.[5]
