Further evidence for the role of IP3R1 in regulating subsynaptic gene expression and neuromuscular transmission

The inositol 1,4,5-triphosphate IP3R channel is highly expressed on specialized ER membrane, where it initiates a slow wave of Ca2+ release from internal stores, allowing subcellular compartmentalization of Ca2+ signals. In skeletal muscle, IP3R1 is also highly concentrated at some myonuclei, particularly near the NMJ. We have reported that in fully developed adult muscle, IP3R1 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 IP3R1 activity in mouse TA muscle by promoting hydrolysis locally of IP3R1 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 IP3R1 in TA muscle increases vesicle trafficking. These studies suggest that postsynaptic IP3R1 activity regulates synaptic gene expression and neuromuscular transmission.