CONUS PEPTIDES AND K CHANNELS

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The vast molecular diversity of K channels has become apparent in the last decade, and it clearly will be an enormous challenge to define the functions of individual molecular forms of K channels. In the last grant period, we uncovered a remarkable diversity of different conopeptide families all apparently targeted to K channels. Remarkably, each clade of Conus species appears to have recruited a different Conus peptide family to target K channels. We will systematically explore four such K channel-targeted Conus peptide families that have been characterized to very different extents: the kappaM-conotoxins, the conkunitzins, the kappaA-conotoxins and the I-superfamily peptides. In the initial phases of the grant period, we will focus first on the kappaM-conotoxins and conkunitzins since the previous characterization of these peptides has been more substantive than for the other groups. Although there is considerable potential in the kappaA-conotoxins and I-superfamily peptides, significant barriers to routine chemical synthesis and folding have to be overcome before these peptides can be systematically characterized. The surprising diversity of the different structural frameworks found in the divergent groups of Conus peptides that target K channels provides the foundation for future structure-function work on a wide diversity of conopeptide:K channel complexes.