The large-conductance calcium-activated potassium channel (BK channel, Slol) is a prominent ion channel at nerve terminals. BK channels co-localize with calcium channels at the presynaptic active zone, and serve as a potent regulator of neurotransmitter release. The function of BK channels is regulated by many factors, suggesting that the channel is potentially an important player in synaptic plasticity. Since proper subcellular localization is likely critical for BK channel function, it is important to determine how BK channel synaptic localization is achieved. Defining the mechanism of BK channel synaptic targeting and localization would be a significant advance in our understanding of synaptic structure and function. In C. elegans, loss-of-function mutations of the BK channel (SLO-1) results in increased neurotransmitter release (Wang et al., 2001), suggesting that the normal function of SLO-1 is to downregulate the release. Similar to BK channels of other species, SLO-1 is localized to synaptic regions in the nervous system (Wang et al., 2001). This restricted distribution pattern was changed to diffuse expression in neurons following a modification of the SLO-1 carboxyl terminus. This proposal seeks to test the hypothesis that presynaptic localization of BK channels is mediated by specific transport and scaffold molecules. Specifically, a genetic screen will be performed to isolate mutants showing mislocalization of a GFP-tagged SLO-1 transgene in C. elegans. Analysis of these mutants in subsequent studies may allow the identification of molecules mediating SLO-1 synaptic targeting and localization.
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