Our project focuses on how potassium ion channels are modified by the actions of lipids including polyphosphoinositides and polyunsaturated fatty acids. These two classes of lipids are structural components of the cellular membrane and also act as lipid signals following certain forms of cellular communication. The fatty acids are present in oily fish, and their consumption is promoted as part of a healthy heart diet. This research has important health implications for how lipid signals impact the proper rhythmicity of heart muscle, neuronal firing patterns, memory disorders, pain and anesthesia, epilepsy, and ischemic damage during stroke and heart attack. To better understand the molecular basis for how these lipids regulate the electrical activity of cells, we will study two channels known as Kir and K2P. We use channels cloned from sponges, a valuable animal model organism, because they give us a way to understand human ion channels by comparative analysis. We will determine how the Kir channel from sponge is regulated by different polyphosphoinositides and compare this to the effects of these lipids on vertebrate ion channels. We found that the Kir channels can be modified by activating enzymes that add phosphate groups to proteins; we will determine how this phosphorylation event may interact with the regulation of the channel by lipid signals. We made a computer model of the sponge Kir channel, at the atomic level, based on atomic structural data for vertebrate Kir channels. We use this model to help predict how the lipids interact with the channel, how phosphorylation may interact with the lipids, and what specific parts of the channel may be important in determining the type of lipid that can interact with the channel. We also plan to measure the lipids in sponge cells and to investigate information in the sponge genome to predict which of the different types of these lipids may exist in the native environment of the channels. For a second type of channel known as K2P, we found that opening of the sponge channel requires the fatty acid, arachidonic acid. Previous work on fatty acid effects in vertebrate channels has implicated a certain region of the K2P channel. We will examine the role of this region for the sponge K2P channel activation by fatty acids using molecular approaches and electrophysiology. Overall, this project will help us better understand the structure-function relationships of lipid signals and ion channels. The principal investigator s an experienced ion channel biologist who has successfully mentored 40 undergraduate research students in almost 10 years at the University of Richmond. In addition to the research goals, this project provides undergraduates with meaningful research experiences and they contribute to biomedically important research, which is the main goal of the AREA grant program.
Our project addresses the molecular basis for the regulation of certain potassium ion channels by lipids or fats which are important structural components of cell membranes and/or important in the diet. How the lipids control the ion channels is important for health and disease because the channels function in memory disorders, pain, stroke, heart attack, and the regulation of salt concentrations in the body. A better understanding of how certain lipids modify the function of ion channels 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|