Further evidence for the role of IP 3R 1 in regulating subsynaptic gene expression and neuromuscular transmission.

The inositol 1,4,5-triphosphate IP 3R channel is highly expressed on specialized ER membrane, where it initiates a slow wave of Ca ( 2+) release from internal stores, allowing subcellular compartmentalization of Ca ( 2+) signals. In skeletal muscle, IP 3R 1 is also highly concentrated at some myonuclei, particularly near the NMJ. We have reported that in fully developed adult muscle, IP 3R 1 knockdown by siRNA increases synaptic strength at both pre- and post-synaptic sites of neuromuscular transmission, increasing both the amplitude and frequency of spontaneous quantal events and quantal content, as well as expression of AChR subunits and other NMJ-specific genes. Here, we demonstrate that reducing IP 3R 1 activity in mouse TA muscle by promoting hydrolysis locally of IP 3R 1 also amplifies expression of subsynaptic genes and transcription factors. Furthermore, using a retrograde tracer, cholera toxin B subunit, we find that siRNA-mediated silencing of IP 3R 1 in TA muscle increases vesicle trafficking. These studies suggest that postsynaptic IP 3R 1 activity regulates synaptic gene expression and neuromuscular transmission.