Synthesis and Stabilization of Postsynaptic Receptors
Muscle tissue is formed from the mesoderm and initially appear
as myoblasts. The myoblasts fuse to produce myotubes, which therefore have multiple
nuclei. As the myotubes mature, the sarcomere, which is the contractile element
of the muscle consisting of actin and myosin, develops. The protein, β-integrin,
seems essential for myoblast fusion and sarcomere assembly.[44]
Shortly after, the motor nerve axons grow into the developing muscle, and these
axons bring in nerve-derived signals (i.e., growth factors), including agrin, that
are key to maturation of the myotubes to muscle.[45]
Agrin is a protein from the nerve that stimulates postsynaptic differentiation by
activating muscle-specific kinase (MuSK), a tyrosine kinase expressed selectively
in muscle. With signaling from
Figure 22-5
Diagram of agrin- and ARIA/neuregulin-dependent events
during neuromuscular junction maturation. After establishment of a nerve on the
muscle, growth factors, including agrin and ARIA (acetylcholine receptor-inducing
activity), are released. Agrin interacting with its receptor MuSK (muscle-specific
kinase) enhances the clustering of the synaptic proteins, including acetylcholine
receptors (AChRs), rapsyn, and ERBB receptors. ARIA is the best candidate for involvement
in the conversion of γ-subunit-containing immature receptor to epsilon-subunit-containing
mature (innervated) receptor, which is synapse specific and therefore not inserted
in the extrajunctional area.
agrin, the acetylcholine receptors, which have been scattered throughout the muscle
membrane, cluster at the area immediately beneath the nerve. Agrin together with
other growth factors called neuregulins also induce the clustering of other critical
muscle-derived proteins, including MUSK, rapsyn, and ERBB proteins, all of which
are necessary for maturation and stabilization of the acetylcholine receptors at
the junction ( Fig. 22-5
).
Just before and shortly after birth, the immature, γ-subunit-containing acetylcholine
receptors are converted to the mature, epsilon-subunit-containing receptors. Although
the mechanism of this change is unclear, a neuregulin (growth factor) called ARIA
(for acetylcholine receptor-inducing activity), which binds to one of the ERBB receptors,
seems to play a role.[46]
