MOLECULAR AND FUNCTIONAL STUDIES OF MAXIK CHANNELS

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DESCRIPTION (adapted from the applicant's description): This competitive renewal application proposes to further examine the structural, cellular and genetic mechanisms of MaxiK channel function. The main hypothesis centers on the idea that maxiK function is regulated by beta subunit association. The questions to be addressed include the following. 1) How do the alpha subunit domains move during activation and how do the beta subunits influence this movement? 2) How do tyrosine kinases influence alpha/beta interaction? 3) What is the structure of the alpha subunit C-terminus? 4) What are the signals for apical sorting of the alpha subunit? 5) What is the impact of deleting the alpha and/or beta subunits from a transgenic mouse? The proposed specific aims are: 1) Define the movement of different regions of the alpha subunit using fluorescent probes, and their modification by the beta 1 subunit. 2) Investigate the mechanism of c-Src modulation of alpha/beta complexes. 3) Perform large-scale purification of the alpha subunit carboxyl end with the goal to crystallize it. 4) Investigate the alpha/beta subunit polarized sorting in MDCK cells. 5) Obtain alpha and beta knockout mice and investigate the impact on neuronal and vascular tissues.