This project has the goal of understanding the allosteric modulation, through voltage sensing, of voltage-gated ion channels and GPCRs has on their function. Allosteric modulation of voltage-gated ion channels occurs via domains not directly needed for voltage sensing and gating, that is, the first three transmembrane domains of each monomer, and the linker attaching this domain to the remainder of the protein. Allosteric modulation of GPCR activity occurs through voltage-sensing. Engineered versions of the Shaker potassium channel and the muscarinic acetylcholine receptor type 2 will be expressed in Xenopus oocytes and probed using electrophysiological and fluorescent techniques.
The aims are to understand the role the linker between the third and fourth transmembrane domains of voltage-gated potassium channels plays in its function, to understand the movements that occur in the second and third transmembrane domains upon changes in membrane potential, independent of the movement of the primary voltage sensor in the fourth transmembrane domain, and to understand the movements that occur in response to changes in membrane potential in GPCRs. The long-term objectives of this project are to advance our understanding of potential novel targets for therapeutics targeted to modulate the voltage-sensing properties of voltage-gated ion channels and GPCRs. As these membrane proteins are already successful targets for many therapies, improved understanding of how to modulate their function should lead towards improvements of human health.

Public Health Relevance

Voltage-gated ion channels and GPCRs are voltage-sensitive membrane proteins;their proper functioning is crucial for appropriate signaling between cells, for the activity of the brain, and for the beating of the heart. Understanding the movements these membrane proteins make in response to electrical changes, and which parts of the proteins are necessary for the protein to function correctly, will greatly improve the ability to produce novel therapies and drugs that target these proteins.

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)
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Silberberg, Shai D
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University of Chicago
Schools of Medicine
United States
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Barchad-Avitzur, Ofra; Priest, Michael F; Dekel, Noa et al. (2016) A Novel Voltage Sensor in the Orthosteric Binding Site of the M2 Muscarinic Receptor. Biophys J 111:1396-1408
Treger, Jeremy S; Priest, Michael F; Bezanilla, Francisco (2015) Single-molecule fluorimetry and gating currents inspire an improved optical voltage indicator. Elife 4:e10482
Labro, Alain J; Priest, Michael F; Lacroix, Jérôme J et al. (2015) Kv3.1 uses a timely resurgent K(+) current to secure action potential repolarization. Nat Commun 6:10173
Treger, Jeremy S; Priest, Michael F; Iezzi, Raymond et al. (2014) Real-time imaging of electrical signals with an infrared FDA-approved dye. Biophys J 107:L09-12
Priest, Michael F; Lacroix, Jérôme J; Villalba-Galea, Carlos A et al. (2013) S3-S4 linker length modulates the relaxed state of a voltage-gated potassium channel. Biophys J 105:2312-22
Shapiro, Mikhail G; Priest, Michael F; Siegel, Peter H et al. (2013) Thermal mechanisms of millimeter wave stimulation of excitable cells. Biophys J 104:2622-8