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synaptic activity actually inhibits AChR synthesis in
the extrasynaptic region. For example, when adult cat
muscle is denervated, the muscle cells become highly
responsive to ACh applied at any position along the
surface. This is referred to as denervation supersensi-
tivity, and it requires new receptor synthesis (Axelsson
and Thesleff, 1959; Merlie et al., 1984). Denervation
supersensitivity can also be produced by decreasing
the transmission of an intact terminal (Figure 8.26).
When presynaptic action potentials are blocked or
cholinergic transmission is eliminated, there is a dra-
matic increase in AChRs (Lømo and Rosenthal, 1972;
Berg and Hall, 1975). The oppositive manipulation,
direct electrical stimulation of muscle cells in vitro,
produces a decrease in AChR synthesis (Shainberg and
Burstein, 1976). At least in muscle cells, synaptic activ-
ity limits receptor synthesis through increasing post-
synaptic calcium (Figure 8.26). The effect may depend
in part on the CaMKII activation and phosphorylation
of the muscle transcription factor, myogenin (Klarsfeld
et al., 1989; Laufer et al., 1991; Huang et al., 1992; Tang
et al., 2004).
Asimilar sort of regulation probably occurs in
neurons. Unlike the NMJ, supersensitivity cannot be
observed as directly in the central nervous system
because neurons are embedded in a web of glia, ECM,
and blood vessels. However, many areas of the
nervous system express high levels of the NMDA
receptor during development, and this expression
seems to be regulated by innervation. For example, the
functional expression of NMDA receptors decreases
with age in the visual cortex of normal kittens, but
when animals are reared in complete darkness to
decrease visually driven activity, NMDAR-mediated
transmission remains at an unusually high level (Fox
et al., 1992). Similar sorts of observations have been
made for AMPA receptors.
A
Axon
ACh
AChR
Muscle fiber
P
Ca +2
CaMKII
myogenin
AChR mRNA
Synaptic nucleus
Non-synaptic nuclei
TTX cuff
B
CaMKII
FIGURE 8.26 Extrasynaptic ACh receptors accumulate when the
nerve is inactive. A. At the control nerve-muscle junction, the elec-
trically active terminal releases ACh and the receptors are clustered
at the postsynaptic membrane. The activity-dependent signal that
suppresses extrajunctional receptors involves calcium influx and
activation of the calcium calmodulin-dependent protein kinase II
(CamKII). A transcription factor found in muscle (myogenin) is
phosphorylated and blocks transcription in extrasynatpic nuclei. B.
When motor axon activity is blocked with the sodium channel
blocker, tetrodotoxin (TTX), extrajunctional ACh receptors are dis-
tributed over the entire muscle surface. (Adapted from Lømo and
Rosenthal, 1972)
NEUREGULIN, A REGULATOR OF
P OSTSYNAPTIC TRANSCRIPTIO N
If synaptic activity represses receptor synthesis,
how does the presence of motor nerve terminals cause
an increase AChR synthesis by the postsynaptic
muscle cells? Neonatal AChRs are initially composed
of four subunits, a 2 bgd, but during the first two post-
natal weeks in rat, the many nuclei beneath each
synapse stop expressing the g-subunit (Figure 8.27A).
There is a gradual increased expression of e-subunit
transcripts, resulting in a new heteromeric receptor,
a 2 bed (Gu and Hall, 1988). The basal lamina has pre-
viously been shown to also contain a signal that
activates AChR transcription in the absence of motor
nerve terminals (Goldman et al., 1991).
An initial screen of soluble factors present in the
chick brain revealed a substance that could stimulate
AChR synthesis in isolated myotubes (Jessell et al.,
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