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Summary: Youxing Jiang, using a combination of structural, biochemical, and electrophysiological methods, probes the functioning of channels that transport ions across cell membranes.

Ion channels are membrane proteins that control the flow of ions such as K⁺, Na⁺, Ca²⁺, and Cl^– across the cell membrane. They regulate many biological processes, such as the excitation of nerve and muscle cells, the secretion of hormones, and sensory transduction. In humans, ion channels are found in nearly all tissues and perform a wide variety of tasks. Because of their prevalence and importance in the human body, ion channel dysfunction lies at the heart of a wide range of human pathologies.

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, whereby the opening and closing of the channel pore is regulated in response to a specific stimulus. My 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 flow across the cell membrane.

	Figure 1: Structure of MthK... Figure 2: Structure of NaK...

To study channel gating, my lab focuses on a group of ligand-gated K⁺ channels that are regulated by a conserved ligand-binding domain, the RCK domain. Our study of cation channel selectivity is focused on voltage-gated Na⁺ channels and nonselective cation channels. Our research will combine membrane protein crystallography, aimed at determining the three-dimensional crystal structures of these channels, and channel electrophysiology, aimed at studying their biophysical properties.

Ligand Gating in K⁺ Channels
Ligand-gated K⁺ channels open in response to the binding of specific ligand molecules. Despite the structural diversity required for different ligands, most ligand-binding domains in K⁺ channels are located at the carboxyl terminus of the pore, close to the end of the pore-lining inner helices. This common position suggests a general mechanism used to convert the chemical energy of ligand binding to the mechanical work of opening the channel.

Analysis of K⁺ channel sequences reveals that the majority of prokaryotic K⁺ channels contain the RCK domain, a conserved C-terminal ligand-binding domain named for its role in regulating the conductance of K⁺. Structure-based sequence alignment and mutagenesis studies have shown that RCK domains also exist at the intracellular C-terminal side of the eukaryotic high-conductance Ca²⁺-gated K⁺ channels (BK or maxiK) as two tandem copies. The wide distribution of RCK domains in K⁺ channels highlights their importance in regulating the flow of K⁺ across the cell membrane. We are using two RCK-regulated K⁺ channels as model systems to study ligand gating in K⁺ channels: a Ca²⁺-activated K⁺ channel, MthK, from the archaebacterium Methanobacterium thermoautotrophicum (Figure 1) and a human high conductance Ca²⁺-gated K⁺ channel (hSlo1). (This research is also supported by grants from the National Institutes of Health and the Robert A. Welch Foundation and a David and Lucile Packard Fellowship.)

Ion Selectivity in Tetrameric Cation Channels
Most tetrameric cation channels, including the K⁺, Ca²⁺, Na⁺, and cyclic nucleotide–gated (CNG) channels, are thought to share a similar overall architecture in their ion conduction pore. Their ion selectivity properties, however, are different. Over the past 10 years, tremendous progress has been made in understanding K⁺ channel selectivity, especially after the structural determination of several K⁺ channels.

There is, however, a severe lack of structural information for other cation channels and, as a result, many of their functional properties—most importantly ion selectivity—are not well understood at the molecular level. Among these channels, the Na⁺ channel and CNG channels stand out for their extreme physiological importance to humans. Detailed structural and functional information about them could lead to breakthrough discoveries not only in the ion channel field but also in medical research as a whole. Another major focus of my research group is elucidating the structural basis of ion selectivity and other functional properties of these two groups of ion channels. Two prokaryotic channels will be used as model systems to study their eukaryotic counterparts: the NaK channel (a prokaryotic nonselective cation channel that is homologous to the ion conduction pore of a CNG channel; Figure 2) and a prokaryotic voltage-gated Na⁺-selective channel. (This research is also supported by grants from the National Institutes of Health, a McKnight Scholar Award, and a David and Lucile Packard Fellowship.)

Last updated July 01, 2008