The long-term objective of this proposal is to expose basic molecular mechanism by which ion channels operate. Potassium channels transfer K+ ions across membranes and in this capacity they are central to the function of all cells, not only muscles and nerves. The structural bases for the function and dysfunction of these critical membrane proteins are only now being uncovered. Recent advances in molecular biology and high-resolution techniques for studying channels have combined to kindle an explosion of new information about how structure, mediates function. The minimal K+ channel (minK) is uniquely suited for this type of analysis. As its name suggests, it is the smallest eukaryotic channel protein known. Despite its apparent simplicity, the channel is voltage-gated, K+-selective and tightly-regulated. Indeed, minK appears critical to both cardiac and auditory electrical activity. This project has four specific aims that attempt to uncover basic structural elements of minK function through study of the residues that line its conduction pore, the sites that mediate open-channel blockade and the channel's subunit composition. The minimal K+ channel merits this type of investigation because of its role in mammalian physiology and its potential to reveal important principles of channel function through its structural simplicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM051851-03
Application #
2749991
Study Section
Physiology Study Section (PHY)
Project Start
1996-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Levy, Daniel I; Cepaitis, Egle; Wanderling, Sherry et al. (2010) The membrane protein MiRP3 regulates Kv4.2 channels in a KChIP-dependent manner. J Physiol 588:2657-68
Dementieva, Irina S; Tereshko, Valentina; McCrossan, Zoe A et al. (2009) Pentameric assembly of potassium channel tetramerization domain-containing protein 5. J Mol Biol 387:175-91
Soh, Heun; Goldstein, Steve A N (2008) I SA channel complexes include four subunits each of DPP6 and Kv4.2. J Biol Chem 283:15072-7