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Sci. STKE, 8 February 2005
Vol. 2005, Issue 270, p. tw55
[DOI: 10.1126/stke.2702005tw55]

EDITORS' CHOICE

ION CHANNELS A Polar Pathway for the S4 Arginines

Voltage-gated ion channels detect changes in transmembrane voltage by means of a specialized voltage-sensing domain through a mechanism that involves movement of positively charged arginines in the S4 helix across the membrane electric field. The precise details of this movement--and whether the S4 arginines reside in a polar protein environment or are exposed to the membrane lipid--have been the subject of some controversy. Tombola et al. found that substitution of the first S4 arginine (R1) of the Shaker potassium channel with smaller amino acids lacking the arginine guanidino group (alanine, cysteine, serine, or valine) enabled passage of an inward current, which they called the "omega current." Pharmacological blockade of the central potassium-conducting pore or closure of the pore through P-type inactivation did not affect the omega current, which was only apparent under conditions in which the S4 segment was in its resting conformation. The current, which could be carried by various cations, was weakly selective for Cs+ over K+ over Li+ and could be carried by guanidinium ions, which suggests that it used the pathway through which arginine sidechains normally move. Mutation of a glutamate residue in the S2 segment that is believed to interact electrostatically with the S4 arginines increased the omega current, whereas extracellular Mg2+ blocked it. The authors conclude that R1 likely faces into a polar protein environment within the voltage-sensing domain and propose a model in which the S4 segment ratchets through conformations in which one arginine after another occupies (and thereby blocks ion permeation through) the narrowest portion of a hydrophilic pore.

F. Tombola, M. M. Pathak, E. Y. Isacoff, Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron 45, 379-388 (2005). [PubMed]

Citation: A Polar Pathway for the S4 Arginines. Sci. STKE 2005, tw55 (2005).

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