Voltage-gated potassium channels are critical components of the machinery for excitability in both muscle and nerves. It is generally accepted that the channel's membrane-spanning core contains the structural elements required for gating and K+ selectivity, while the highly conserved cytoplasmic tetramerization (Tl) domain drives channel tetramerization. However, this general understanding of K+ channel structure is still incomplete. For this project, we propose to use RNA editing in octopus as a guide to identify key functional residues in a voltage-dependent K+ channel, and then to study the precise mechanisms by which these residues affect gating. Basic protein function studies often rely on the introduction of changes into a protein's structure in order to learn how different parts of the protein participate in overall function. Here, we use RNA editing to highlight places in a K+ channel that are important for function. The approach is based on two hypotheses. First, channels isolated from similar organisms that inhabit drastically different thermal environments will have evolved specific structural changes to compensate for temperature's effect on gating kinetics. Second, in octopus these structural changes will be accomplished by RNA editing. In the preliminary data, RNA editing patterns for Kvl channels from an Antarctic and a tropical octopus are presented. mRNAs for each exhibit a unique editing pattern, and three of the editing sites made pronouced changes to channel gating. Two of the sites are located in the cytoplasmic Tl domain and the third lies in the pore domain. In the proposed work, each of these three editing sites will be studied using multiple approaches to determine how they affect gating. Through these experiments we will learn more about how these two domains are involved in channel function. All voltage-gated potassium channels have conserved Tl and pore domains, and a basic understanding of how these domains work is important for studying different channelopathies. Potassium channels are important molecules for muscle and nerve cell function because they regulate the movement of ions across cell membranes. Malfunction of potassium channels is involved in a number of diseases, from heart arrhythmias to epilepsy. Research like the proposed study promotes a basic understanding of how these channels work, which is the basis for determining how different channel related diseases occur and how they may be treated.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03B-H (20))
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Silberberg, Shai D
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University of Puerto Rico Med Sciences
Internal Medicine/Medicine
Schools of Medicine
San Juan
United States
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