THESIS
2013
xii, 81 pages : illustrations ; 30 cm
Abstract
The neuromuscular junction (NMJ) undergoes a maturation process physiologically after
initial nerve-muscle contact, which is characterized by spontaneous synaptic current (SSC)
amplitude increase and rise time decrease, as well as the development of well-defined quantal
ACh release. Chronic application of BDNF and elevation of intracellular cAMP resulted in
inhibition in the maturation process, while NT-3, NT-4, GDNF, HB-GAM and HGF appeared
to promote it. The response to BDNF was mediated by TrkB receptor. PKA inhibitors could
reverse the inhibitory effects of cAMP and BDNF, which suggests that cAMP and BDNF
suppress NMJ maturation through cAMP-PKA-dependent signaling pathway. Further
investigations revealed that CaMKs mediate the inhibitory effects of cAMP and BDNF. That
led...[
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The neuromuscular junction (NMJ) undergoes a maturation process physiologically after
initial nerve-muscle contact, which is characterized by spontaneous synaptic current (SSC)
amplitude increase and rise time decrease, as well as the development of well-defined quantal
ACh release. Chronic application of BDNF and elevation of intracellular cAMP resulted in
inhibition in the maturation process, while NT-3, NT-4, GDNF, HB-GAM and HGF appeared
to promote it. The response to BDNF was mediated by TrkB receptor. PKA inhibitors could
reverse the inhibitory effects of cAMP and BDNF, which suggests that cAMP and BDNF
suppress NMJ maturation through cAMP-PKA-dependent signaling pathway. Further
investigations revealed that CaMKs mediate the inhibitory effects of cAMP and BDNF. That
led us to study the function of Ca
2+ in this regulation. Ca
2+-free culture medium had no effect
on cAMP and BDNF-mediated inhibition of NMJ maturation. However, depletion of
cytosolic Ca
2+ potently reversed the effects, suggesting that Ca
2+ released from intracellular
Ca
2+ stores regulates neurotrophic actions on NMJ maturation. Since Ca
2+ released from
intracellular Ca
2+ stores through IP3 receptors and ryanodine receptors, their roles in
regulating NMJ maturation were studied. In the presence of 2-APB (IP3 receptor inhibitor) or
TMB-8 (ryanodine receptor inhibitor) alone, the inhibitory effects of cAMP and BDNF were still present. However, co-treatment with both 2-APB and TMB-8 reversed their effects,
suggesting that mobilization of intracellular Ca
2+ mediated by either IP3Rs or RYRs
contributes to the effect of cAMP/BDNF in inhibiting NMJ maturation.
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