This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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