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Ion Channels and Transporters

Research Summary

Youxing Jiang, using a combination of structural, biochemical, and electrophysiological methods, probes the functioning of ion channels and transporters, which control the flow of ions across cell membranes.

Our research has been focused on the structural and functional studies of ion channels and transporters, which control the flow of ions across the cell membrane. These proteins regulate many biological processes, such as the excitation of nerve and muscle cells, the secretion of hormones, and sensory transduction. Our approach combines membrane protein x-ray crystallography, to determine the three-dimensional structure of the ion-transporting proteins, and channel electrophysiology, to study the physiological functions of these proteins.

Ion Channels
Ion channels are membrane proteins that, in a regulated fashion, open a hole in the lipid membrane and allow the free diffusion of ions down their electrochemical gradients. Two fundamental properties are central to ion channel function: ion selectivity, whereby only the passage of specific ions is allowed through the channel pore; and channel gating, where the opening and closing of the channel pore is regulated in response to a specific stimulus. Our research is aimed at understanding the molecular mechanisms of both channel selectivity and gating in tetrameric cation channels, the single largest family of ion channels. In these channels, four membrane-spanning subunits or domains form a central pore through which specific ions cross the cell membrane.

To study channel gating, we focus on a group of ligand-gated K+ channels that are regulated by a conserved ligand-binding domain, the RCK domain. This group includes the majority of prokaryotic K+ channels and the eukaryotic high-conductance Ca2+-gated K+ channels (BK or maxiK). We are using three RCK-regulated K+ channels as model systems for studying ligand specificity and ligand-induced conformational changes in K+ channels: MthK, a Ca2+-gated K+ channel from Methanobacterium thermoautotrophicum (Figure 1); GsuK, a nucleotide-gated Ca2+-inhibited K+ channel from Geobacter sulfurreducens; and the BK channel (hSlo1), a human high-conductance Ca2+-gated K+ channel.

Another goal of our research is to understand the structural basis of ion selectivity in tetrameric cation channels, using the NaK channel, a nonselective prokaryotic cation channel from Bacillus cereus, as the model system. Taking advantage of the extremely high-resolution crystal structures of NaK and its mutants that represent the ion conduction pores of both selective and nonselective cation channels (Figure 2), we aim to elucidate the basic principles of ion selectivity in two families of physiologically essential cation channels. One family is the nonselective, Ca2+-permeable cyclic nucleotide–gated (CNG) channels, whose functions are central to signal transduction in the visual and olfactory sensory systems; to study this family we use NaK from Bacillus cereus and its CNG-mimicking chimeras as model systems. To study the K+-selective channel family, we use a K+-selective NaK mutant (NaK2K) and the MthK K+ channel from M. thermoautotrophicum as model systems.

Ion Transporters
Distinct from ion channels, ion transporters can move ions across the plasma membrane against the electrochemical gradient. We are expanding our study of ion transporters, which has been focused on Na+/Ca2+ exchangers, to other cation/Ca2+ exchanger proteins.

Na+/Ca2+ exchangers (NCXs) are membrane transporters central in maintaining the homeostasis of cytosolic Ca2+ for cell signaling. They are essential to many physiological processes, including muscle contraction, cell mobility, fertilization, exocytosis, and apoptosis. NCX proteins use the downhill gradient of Na+ to extrude intracellular Ca2+ across the cell membrane against its chemical gradient. Several functional features of an NCX protein define its physiological roles: it can exchange Ca2+ and Na+ with a high-turnover rate; the ion-exchange process is electrogenic, with a stoichiometry of 3 Na+ for 1 Ca2+; and the exchange reaction is bidirectional, depending on the membrane potential and the chemical gradient of Na+ and Ca2+. Despite a large body of functional data, the structural mechanism underlying these functional features remains elusive. With the determination of a high-resolution structure of an NCX protein from Methanococcus jannaschii (NCX_Mj) (Figure 3), we now have a working model system to elucidate the structural basis and mechanistic details of ion exchange in NCX proteins.

This research is also supported by grants from the National Institutes of Health and the Welch Foundation.

As of August 23, 2012

Scientist Profile

Investigator
The University of Texas Southwestern Medical Center
Biophysics, Structural Biology