Ion Transport Across Biological Membranes

All animal cells contain specialized integral membrane proteins that modulate the passage of specific ions through the plasma membrane. The Na⁺/K⁺-ATPase, or sodium pump, is a voltage-gated membrane transport protein found in most higher-order eukaryotic cells and is essential for life. Sodium pumps exchange 3Na⁺ and 2K⁺ ions across the membrane in opposite directions using chemical energy in the form of ATP. The sodium pump is vital to maintaining a transmembrane voltage and plays an essential role in the normal function of various organ systems, particularly the heart, kidney, and brain. Recent evidence has linked mutations of the sodium pump to two human disorders -- familial hemiplegic migraine and rapid-onset dystonia parkinsonism. Savas Kaya, associate professor of electrical engineering, leads a collaborative effort to obtain molecular and physical-chemical level understanding of the mechanism of ion translocation bythe sodium pump. Kaya's group focuses especially on the development of computer simulations and modeling techniques to aid experimentalists in the departments of Biological Sciences (Ralph DiCaprio) and Physics and Astronomy (Saw Hla) who utilize electro-physiological measurements and scanning electron microscopy, respectively, to study the structure-function relationship ofthis protein. Kaya's group develops structural models via homology and employs particle (MD, Brownian dynamics, etc.) and continuum transport models to predict the effect of mutations in amino acid sequence of the alpha subunit of the sodium pump and ion transport/occlusion processes. These predictions can be tested by electrical current experiments performed on Xenopus oocytes injected with mutated cRNA. Changes in ion binding affinity and the voltage dependence of individual charge-translocating steps in the pump cycle are measured using various voltage clamp techniques. Kaya's group is also developing the capability of using measurements of changes in fluorescence under voltage clamp conditions to track changes in the conformation of the pump protein during various partial reactions of the pump cycle. Ultimately, the fundamental insights gained from these studies are expected to guide the development of biomimetic sensors and molecular devices for logic computation and storage.