DEVELOPMENT AND MAINTENANCE OF THE NEUROMUSCULAR JUNCTION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 多年来，我们的工作一直专注于神经肌肉接头的发育和维持。我们最近对抗疟药甲氟喹（Lariam）的研究表明，自发和刺激诱发的递质释放在成人神经肌肉接头处受到不同的调节。也就是说，甲氟喹选择性地增加自发的，但不是刺激诱发的，囊泡释放。甲氟喹的这种作用依赖于细胞内而非细胞外钙。这种细胞内钙的来源可能是运动神经末梢的线粒体，因为甲氟喹与寡霉素一样，抑制这些细胞器的FOF 1H +- ATP合酶。因此，我们的工作假设是，异步发射器释放可能是一个能量传感系统的一部分，对神经肌肉接头的健康和稳定至关重要。虽然这一假设对我们工作的长期目标很重要，但它与我们的糖尿病研究高度相关。在糖尿病中，神经肌肉接头经历有害的形态和功能改变。可以想象，这些变化是继发于糖尿病引起的神经肌肉接头能量平衡的改变。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For many years, our work has focused on the development and maintenance of the neuromuscular junction. Our very recent study of the antimalaria drug mefloquine (Lariam) suggests that spontaneous and stimulus-evoked release of transmitter are differentially regulated at the adult neuromuscular junction. That is, mefloquine selectively increases spontaneous, but not stimulus-evoked, vesicular release. This effect of mefloquine is dependent upon intracellular but not extracellular calcium. The source of this intracellular calcium may be mitochondria of motor nerve terminals since mefloquine, like oligomycin, inhibits the FOF1H+- ATP synthase of these organelles. Thus, our working hypothesis is that asynchronous transmitter release may be part of an energy sensing system essential to the health and stability of the neuromuscular junction. While this hypothesis is important to the long-term goal of our work, it is highly relevant to our studies of diabetes. In diabetes the neuromuscular junction undergoes deleterious morphological and functional alterations. It is conceivable that these changes are secondary to diabetes-induced alterations of energy balance at the neuromuscular junction.