Abstract
The P/Q-type voltage-dependent calcium channels (VDCCs) are essential for synaptic transmission at adult mammalian neuromuscular junctions (NMJs); however, the subsynaptic location of VDCCs relative to active zones in rodent NMJs, and the functional modification of VDCCs by the interaction with active zone protein Bassoon remain unknown. Here, we show that P/Q-type VDCCs distribute in a punctate pattern within the NMJ presynaptic terminals and align in three dimensions with Bassoon. This distribution pattern of P/Q-type VDCCs and Bassoon in NMJs is consistent with our previous study demonstrating the binding of VDCCs and Bassoon. In addition, we now show that the interaction between P/Q-type VDCCs and Bassoon significantly suppressed the inactivation property of P/Q-type VDCCs, suggesting that the Ca2+ influx may be augmented by Bassoon for efficient synaptic transmission at NMJs. However, presynaptic Bassoon level was significantly attenuated in aged rat NMJs, which suggests an attenuation of VDCC function due to a lack of this interaction between VDCC and Bassoon. Importantly, the decreased Bassoon level in aged NMJs was ameliorated by isometric strength training of muscles for two months. The training increased Bassoon immunoreactivity in NMJs without affecting synapse size. These results demonstrated that the P/Q-type VDCCs preferentially accumulate at NMJ active zones and play essential role in synaptic transmission in conjunction with the active zone protein Bassoon. This molecular mechanism becomes impaired by aging, which suggests altered synaptic function in aged NMJs. However, Bassoon level in aged NMJs can be improved by muscle exercise.
Highlights
Synaptic transmission at the adult neuromuscular junctions (NMJs) initiates by the Ca2+ influx through the P/Q-type voltage-dependent calcium channels (VDCCs) [1,2] and synaptic vesicle fusion at the active zones [3]
We have demonstrated that VDCCs utilize their cytosolic domain to bind active zone proteins, which localize as discrete small puncta in NMJs
We show that P/Q-type VDCCs localized in a discrete punctate pattern in the presynaptic terminals of NMJs and co-localized with the Bassoon
Summary
Synaptic transmission at the adult NMJs initiates by the Ca2+ influx through the P/Q-type VDCCs [1,2] and synaptic vesicle fusion at the active zones [3]. We tested P/Q-type VDCCs using patch-clamp recording and demonstrated that the interaction of P/Q-type VDCCs and Bassoon modifies the VDCC function This modification has the potential to play an important role in synaptic transmission at NMJs. This modification has the potential to play an important role in synaptic transmission at NMJs If this interaction is essential for NMJ synaptic transmission, our recently findings of attenuated Bassoon protein levels in aged mouse NMJs may have deleterious effects on the NMJ function [15]. This view is consistent with the physiological alterations recorded at aged NMJs by others [25,26,27] and may be related to denervation of aged NMJs [25,28,29,30]. We identified that Bassoon level can be recovered in aged NMJs by muscle training
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