Heads of Laboratories
Cell membranes contain millions of embedded proteins that control ion movements into and out of the cell. This ion flow underlies such vital functions as electrical signaling in nerve, heart and muscle cells, cell volume regulation, secretion of hormones and neurotransmitters, fertilization and kidney function. Dr. Gadsby’s research focuses on how ion transport proteins work.
Two principal classes of proteins regulate ion movement across membranes: pumps and channels. Although both move ions through the cell’s otherwise impenetrable phospholipid bilayer, they play distinct roles. Channels allow ions to flow rapidly down their electrochemical gradients, while pumps move ions relatively slowly, thermodynamically uphill, thereby building up those gradients. Pumps and channels have therefore traditionally been viewed as very different entities. Dr. Gadsby’s work, however, suggests that these membrane proteins are far more closely related than generally assumed.
The Gadsby lab is using position-specific mutagenesis, combined with structural modeling and biochemical and electrical measurements, to examine the mechanisms of two biomedically important ion transport proteins. One, the Na+/K+-adenosine triphosphatase, is a pump, and the other, the cystic fibrosis-linked protein known as CFTR (cystic fibrosis transmembrane conductance regulator), is a Clion channel. The Na+/K+ pump establishes the transmembrane gradients of Na+ and K+ ions that are crucial to animal cell life, whereas CFTR channels conduct Cl- ions across the membranes of epithelial cells, allowing the simultaneous movement of water. Mutations in the gene that encodes CFTR are responsible for cystic fibrosis, the most prevalent lethal genetic disease in the United States. Mutations in the Na+/K+ pumps of neurons in the brain have recently been found responsible for neurological disorders in children.
Research from the Gadsby lab suggests that, just as an ion channel can be viewed as an ion pathway that is controlled by a gate, an ion pump can be viewed as a modified ion channel controlled by two gates: The gates in a pump must be tightly coupled so that they are never both open at the same time. From this perspective, the conformational changes that open and close the ion pathway gates in the two kinds of ion transport need not be all that different. Indeed, in both the Na+/K+ pump and CFTR Cl- channel, these conformational changes are driven by binding and hydrolysis of adenosine triphosphate (ATP).
In work on CFTR, lab members use the sensitive patch-clamp recording technique to analyze the timing of the opening and closing of individual wild-type and mutant CFTR channels as they’re exposed to ATP and/or nucleotide analogues. So far, they have found that ATP binds to both of the nucleotide-binding domains in a single CFTR molecule before the gate in its channel opens, that the two binding sites interact to regulate each other’s function and that one of them acts like a G protein: The nucleotide bound there stabilizes the active, open-channel conformation until its hydrolysis prompts channel closure. From such findings, the Gadsby lab has recently detailed the accepted model for how the opening and closing of the CFTR ion channel is regulated, furthering scientific understanding of the origins of cystic fibrosis.
In work on the Na+/K+ pump, a marine toxin has been used that interferes with the strict coupling between the pump’s two gates. When the toxin is bound to the pump, the two gates are occasionally allowed to both be open, thereby transforming the pump into an ion channel. Dr. Gadsby is currently exploiting this action to probe the nature of the ion pathway through the Na+/K+ pump as well as the nature and control of its gates. In work on unmodified native Na+/ K+ pumps, Dr. Gadsby and colleagues have shown that the pumps release three Na+ ions to the cell exterior in three distinct, obligatorily sequential, gating steps, with progressively faster speeds. Most recently, the Gadsby lab has found that during the normal Na+/K+ transport cycle, certain conformations of the Na+/K+ pump can be transiently hijacked by extracellular protons, which use the pump to gain access to the cell interior.
Dr. Gadsby received his bachelor’s degree in 1969 and his master’s in 1973, both in physiology and biophysics from the University of Cambridge, where he attended Trinity College. He graduated with a Ph.D. in physiology from University College London in 1978. Dr. Gadsby came to Rockefeller in 1975 to finish his studies with Paul F. Cranefield in the Laboratory of Cardiac Physiology. He was promoted to assistant professor in 1978, associate professor in 1984 and professor in 1991.
Dr. Gadsby received a MERIT Award from the National Institutes of Health in 1998, a K.S. Cole Award from the Biophysical Society in 1995 and an Irma T. Hirschl Career Scientist Award in 1986. In 2005, he was elected a fellow of The Royal Society.
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