The fundamental principles underlying voltage sensing, a hallmark feature of electrically excitable cells, are still enigmatic and the subject of intense scrutiny and controversy. This is precisely the gap in knowledge the program intends to fill. The ultimate goal of this endeavor is the understanding of the mechanism of voltage sensing based on the modular design of voltage-gated channel proteins. Major objectives are: to define the protein fold(s) best suited to fulfill the pivotal function of voltage sensing;to delineate a minimum set of determinants sufficient for sensing;to uncover a molecular blueprint for a versatile voltage sensor design for which a finite number of specified perturbations would adapt it to sense a wide range of membrane potential;and to establish the surface compatibility underlying the interaction between the two modules and the propagation of change from one module to the other that produces the exquisite sensitivity of the pore to voltage in intact voltage-gated channels. We propose to characterize the channel properties of the isolated voltage sensor module (VSM), the pore module (PM), and the self-assembled [VSM-PM] complex by overexpression and reconstitution into lipid bilayers and giant proteoliposomes, aiming to recapitulate the functional features of the intact voltage-gated K+ channel (Kv) from its component modules. We propose to explore the voltage sensor sequence landscape approached by generating and screening random libraries of VSM mutants aiming to identify and demonstrate unsuspected channels with new voltage-gating phenotypes. We intend to determine the atomic resolution-structures of KvLm and its modules by X-ray crystallography. Exciting results have already emerged which pave the way for a decidedly productive phase of the program. Overall, the itinerary entails going from modules to sequence, to structure and back to mechanism. This focused and realistic program outlines a novel way of thinking about voltage sensing.

Public Health Relevance

Ion channels, a special class of membrane proteins that allow the selective and regulated diffusion of ions across membranes, are fundamental for cell function and regulation. Their design is a marvel of protein chemistry and evolution, and their dysfunction is at the root of devastating human diseases such as epilepsy and arrhythmia. The voltage sensor, the unique element that endows Na+ and K+ channels, which underlie the nerve action potential with the exquisite sensitivity to transmembrane voltage, remains enigmatic and needs further study. The thrust of our program aims to establish structure-function relationships with a primary emphasis on the modular design of the transmembrane domain in voltage-gated channel proteins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Hagan, Ann A
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Ogiwara, Ikuo; Miyamoto, Hiroyuki; Tatsukawa, Tetsuya et al. (2018) Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice. Commun Biol 1:
Montal, Mauricio (2017) Tetanus neurotoxin: conformational plasticity as an adaptive strategy. EMBO Rep 18:1268-1270
Syeda, Ruhma; Santos, Jose S; Montal, Mauricio (2016) The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine. J Biol Chem 291:2931-7
Syeda, Ruhma; Qiu, Zhaozhu; Dubin, Adrienne E et al. (2016) LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength. Cell 164:499-511
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Montal, Mauricio (2014) Redox regulation of botulinum neurotoxin toxicity: therapeutic implications. Trends Mol Med 20:602-3
Syeda, Ruhma; Santos, Jose S; Montal, Mauricio (2014) Lipid bilayer modules as determinants of K+ channel gating. J Biol Chem 289:4233-43
Fischer, Audrey; Montal, Mauricio (2013) Molecular dissection of botulinum neurotoxin reveals interdomain chaperone function. Toxicon 75:101-7
Santos, Jose S; Syeda, Ruhma; Montal, Mauricio (2013) Stabilization of the conductive conformation of a voltage-gated K+ (Kv) channel: the lid mechanism. J Biol Chem 288:16619-28
Santos, Jose S; Asmar-Rovira, Guillermo A; Han, Gye Won et al. (2012) Crystal structure of a voltage-gated K+ channel pore module in a closed state in lipid membranes. J Biol Chem 287:43063-70

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