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ion channel structure/function
The primary interest of this laboratory is in understanding the physiological roles and functional properties of the BK-type calcium (Ca2+)- and voltage-dependent potassium (K+) channel and its close relatives. BK channels are abundantly expressed in a variety of cell types and play a critical role in coupling changes in submembrane Ca2+ concentration to regulation of cellular excitability. In some cells, BK channels play a primary role in fast action potential repolarization, while in other cells BK channels may serve to retard action potential firing frequency or prevent action potential initiation. BK channels are unique in being regulated by two distinct physiological signals: membrane voltage and cytosolic Ca2+.  Structurally, BK channels (encoded by the Slo1 gene) can be considered to contain two primary domains, the pore domain with strong homologies to other voltage-gated channels and a cytosolic structure, which appears to be the element responsible for regulation by Ca2+.   Thus, voltage regulation and Ca2+ regulation appear to arise from distinct components of the channel. Similarly, a close homologue of the BK channel, the pH-regulated Slo3 channels, exhibits a similar modular structure in which pH-regulation arises from the cytosolic structure.

Using a combination of electrophysiology, molecular biological, and structural approaches, we are investigating how gating of channels in the BK family  is regulated.

First, we are interested in how ligand-binding on the cytosolic structure results in changes in the channel open-closed equilibrium. What are the conformational changes that occur in the cytosolic structure and how do these influence the pore domain? What is different about how voltage-sensing couples to channel opening in comparison to ligand-sensing?

Second, channel opening and closing is generally considered to arise from movement of a pore-lining S6 alpha helix. Although the "S6 gate" closes the cytosolic end of the channel, there is reason to think that a gate must also occur at the other end of the channel pore. We have strong evidence that closing of the channel ivity filter plays an important role in gating for some Slo family members.

Third, we are interested in how auxiliary beta subunits also change channel structure and function, including mechanisms of inactivation and modulation of gating.  



Research Photos (Click to Enlarge)

Research Publications

Xia XM, Zhang X, Lingle CJ (2004 Jun 16). Ligand-dependent activation of Slo family channels is defined by interchangeable cytosolic domains. J Neurosci. 24 (24): 5585-91. Full Article >

Zeng XH, Xia XM, Lingle CJ (2003 Jun). Redox-sensitive extracellular gates formed by auxiliary beta subunits of calcium-activated potassium channels. Nat Struct Biol. 10 (6): 448-54. Full Article >

Xia XM, Zeng X, Lingle CJ (2002 Aug 22). Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature. 418 (6900): 880-4. Full Article >

Xia XM, Ding JP, Lingle CJ (2003 Feb). Inactivation of BK channels by the NH2 terminus of the beta2 auxiliary subunit: an essential role of a terminal peptide segment of three hyhobic residues. J Gen Physiol. 121 (2): 125-48. Full Article >

Lingle CJ (2002 Sep). Setting the stage for molecular dissection of the regulatory components of BK channels. J Gen Physiol. 120 (3): 261-5. Full Article >

Wang YW, Ding JP, Xia XM, Lingle CJ (2002 Mar 1). Consequences of the stoichiometry of Slo1 alpha and auxiliary beta subunits on functional properties of large-conductance Ca2+-activated K+ channels. J Neurosci. 22 (5): 1550-61. Full Article >

Contact Info
Chris Lingle, Ph.D.
Office Location: 5552 Clinical Sciences Bldg.
Office Phone: 314-362-8558
Lab Phone: 314-362-8559
Campus Box: 8054
Fax: 314-362-8571

clingle@morpheus.wustl.edu
http://elysium.wustl.edu/cllab/