The goal of our research is to determine the molecular mechanisms of chloride-selective ion channels and transporters.  To approach this we use a unique combination of biophysical methods to probe protein structure and dynamics together with electrophysiological analysis to directly measure function. 

Ion transport across the hydrophobic barrier of the cell membrane is a primary challenge faced by all cells.  Such transport sets up and exploits ion gradients, thus providing the basic energy and signaling events that are the foundation of life.  Ion transport is catalyzed by two classes of membrane proteins: ion channels and active transporters.  Ion channels form passive pores:  they allow ions to move down (and only down) their electrochemical gradients.  Active transporters, on the other hand, use energy to drive ions against their electrochemical gradients.  Primary active transporters use the energy of ATP hydrolysis or light, while secondary active transporters use energy derived from the movement of one ion down its electrochemical gradient to catalyze uphill movement of another ion.  In either case, active transport cannot be accomplished by a passive pore but requires coupling of protein conformational changes to the dissipation of an energy source.  This essential difference has led to the widespread thought that channels and active transporters must be completely different types of proteins operating by fundamentally different mechanisms.  

Our work focuses on a class of proteins known as the CLC family of chloride-transport proteins.  In humans, there are nine CLC proteins which are ubiquitously expressed and necessary for proper cardiovascular, muscular, neuronal, and epithelial function.  From a mechanistic standpoint, the CLC family is unique in containing both ion channels and active transporters.  The existence of both types of transport proteins within one gene family challenges the existing paradigm and long-held assumption that they must operate by radically different mechanisms and suggests instead that their mechanisms may be subtle variations on a single central theme.  By studying ion-transport mechanisms in both types of CLC proteins, we aim to discover how these proteins have evolved to carry out these ostensibly different functions; this work promises not only to clarify our understanding of the CLCs but also to yield new insight into the elemental distinctions and similarities between channels and active transporters.