application) The research: Potassium channels catalyze the movement of K+ ions across the cell membrane. In this fashion they mediate essential cell functions, such as setting resting membrane potential, modulating action potential duration and maintaining fluid and electrolyte homeostasis. We propose here to study hTPKC I from human brain, a novel member of the recent superfamily of K+ channels that are characterized by the presence of two pore forming loops within each channel subunit. In Xenopus oocytes hTPKC1 induces K+ selective and outwardly rectifying currents. In yeast cells deleted for their K+ transporters, hTPKC1 confers the ability to survive on potassium-limiting medium. We plan to investigate the structure and function of hTPKC1 by combining the powerful tools of yeast genetics and channel electrophysiology. The candidate: Dr. Detlef Bockenhauer is a pediatric nephrologist with a long-held interest in physiology that motivated his training in nephrology (Yale) after his pediatric residency (NYU). His career goal is to run a basic research laboratory investigating the mechanistic principles of ion channel function and their implications for human diseases. This proposal is submitted to support his career development in the disciplines of biophysics and molecular biology to enable him to become an independent investigator and academically viable clinician-scientist. The environment: The primary sponsor, Dr. Steve Goldstein, is a leading investigator potassium channel research and ion channelopathies. The first member of the 2 P domain superfamily and many homologues were first cloned and expressed in his laboratory, which is rich in biophysical, molecular biology and molecular genetic expertise. The Departments of Physiology and Pharmacology at Yale is staffed with an internationally recognized cadre of ion channel researchers.
