Our project focuses on modulation of potassium ion channels by membrane-derived polyunsaturated fatty acids (PUFAs) such as arachidonic acid. PUFAs are important dietary lipids and are released from the membrane as lipid signals following certain forms of cellular communication. Voltage-gated Kv4 channels are important in rhythmic firing, learning, and excitability of the heart. They are implicated in disease states such as epilepsy, pain, memory disorders, and cardiac arrhythmia. TREK and TRAAK channels are PUFA- and mechanosensitive members of the K2P family of potassium channels. K2P channels are important in maintaining the resting excitability of cells and opposing increases in excitability. They are implicated in sensing membrane stretch and osmotic changes and may provide protection against ischemic damage. PUFAs modify the activity of both of these types of potassium channels and our research goal is to determine how this occurs at the molecular level so that we can understand how lipid signals impact neural activity. We will study the ion channels by electrophysiology and will use structural models, computational work, and molecular modifications of the channels to reach our research goal. We will determine how PUFAs interact with different gating states or shape changes of the Kv4 channel. To test this at the molecular level, we will make structural changes that alter how the channels function and will measure the impact on PUFA effects on the channel. We will examine the relationship between changes in membrane stretch and the effects of PUFAs. Finally, we will use a structural model of the channel which we built to identify possible lipid binding pockets on the channel. For K2P channels, how PUFAs open the channels will be tested by strategic use of a novel K2P channel cloned from a marine sponge which is distantly related to the mammalian channels. Our preliminary data suggest that the sponge channel is sensitive to PUFAs but not to mechanical forces in the membrane;this is in contrast to the TREK and TRAAK mammalian K2P channels which simultaneously possess sensitivity to PUFAs and membrane stretch. Molecular and physiological comparisons of the sponge and mammalian channels will be used to identify the structural regions that are required and sufficient for PUFA sensitivity. Because K2P channels are regulated by another lipid signal, PIP2, we will assess possible physiological interactions of the two lipids on the K2P channels. The principal investigator is an experienced ion channel biologist who has successfully mentored 24 undergraduate research students in 6 years at the University of Richmond. Her lab provides an excellent environment for undergraduates to pursue their interests in biomedical research. In addition to the research goal, a second goal of this project is to provide undergraduate students with valuable opportunities to participate actively in the scientific process by engagement in this research program.
Our project addresses the molecular basis for the regulation of certain potassium ion channels by PUFAs, omega-3 fatty acids which are important structural components of cell membranes and important dietary lipids. This research has important health implications for how lipid signals impact the proper rhythmic firing of heart muscle and some regions of the brain, memory disorders, pain, ischemic damage during stroke and heart attack, and the physiological and pathological consequences of membrane stretch and changes in tissue salt concentration. A better understanding of how certain lipid signaling molecules alter cellular excitability is an important goal in biomedical research.
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| Corbin-Leftwich, Aaron; Small, Hannah E; Robinson, Helen H et al. (2018) A Xenopus oocyte model system to study action potentials. J Gen Physiol 150:1583-1593 |
| Tang, Qiong-Yao; Larry, Trevor; Hendra, Kalen et al. (2015) Mutations in Nature Conferred a High Affinity Phosphatidylinositol 4,5-Bisphosphate-binding Site in Vertebrate Inwardly Rectifying Potassium Channels. J Biol Chem 290:16517-29 |
| Heler, Robert; Bell, Jessica K; Boland, Linda M (2013) Homology model and targeted mutagenesis identify critical residues for arachidonic acid inhibition of Kv4 channels. Channels (Austin) 7:74-84 |
| Wells, Gregory D; Tang, Qiong-Yao; Heler, Robert et al. (2012) A unique alkaline pH-regulated and fatty acid-activated tandem pore domain potassium channel (K?P) from a marine sponge. J Exp Biol 215:2435-44 |
