In excitable cells, voltage-gated potassium channels play an important role in regulating the duration of the action potential. We hypothesize that the targeting of channels to particular membrane microdomains and their organization in macromolecular complexes allow cells to increase the efficiency of their response to extracellular signals. The work proposed in this application is directed towards understanding the molecular mechanisms underlying the trafficking and turnover of Kv1.5 and KV2.1 potassium channels. We propose to characterize the macromolecular complex (channelosome) that modulates the function of a delayed rectifier potassium channel, Kv1.5. We will use a combination of biochemical and molecular tools, patch-clamp analyses, and in vivo mouse models to pursue the following specific aims: (1) To determine the mechanisms that regulate trafficking of Kv1.5 polypeptide to caveolae, specifically to characterize the interactions between Kv1.5 and caveolin-3 (Cav-3) and SAP97. (2) To examine the role of posttranslational modifications on the trafficking, assembly, and stability on Kv1.5/Cav-3/SAP97 macromolecular complex. To map the site of interactions between SAP97 and Cav-3 and prove that this interaction contributes to the targeting of Kv1.5 to caveolae. (3) To characterize the role of N-terminal cysteines of Kv2.1 and their posttranslational modifications in regulating the assembly, trafficking, and gating of Kv2.1. The work outlined in this application should greatly increase our understanding of the regulation of expression of Kv1.5 and Kv2.1. ? ?
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