Key Points
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Voltage sensors are structures within a protein that can sense the membrane potential.
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The movement of the sensing charges, combined with the configuration of the electric field, determines the extent of the conformational change that occurs.
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Gating currents, or more generally sensing currents, are the transient currents that are produced by the movement of the sensing charges.
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The K+ channel voltage sensor is described in detail because it has been studied using several biophysical techniques and its crystal structure is available. Biophysical techniques can delineate the details of the movement of the voltage sensor in response to changes in the membrane potential.
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The Na+ channel is responsible for the upstroke of the nerve impulse and differs from K+ channels; it is faster and has intrinsic cooperativity.
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Channels that close on depolarization contain the voltage sensor for segments 1–4 (S1–S4); however, the gate operates in reverse to the classic Na+, K+ and Ca2+ channels. The proton channel is another member of the S1–S4 voltage sensor family, but it lacks a pore region. Another membrane protein that contains the S1–S4 voltage sensor is voltage-dependent phosphatase; here the sensor regulates the activity of its built-in phosphatase.
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Some G-protein coupled receptors are voltage dependent. The membrane potential regulates affinity in the m1 and m2 muscarinic receptors and shows sensing currents.
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The Na–glucose co-transporter is voltage dependent and shows sensing currents; and the Na+−K+ pump is electrogenic and shows sensing currents.
Abstract
The ionic gradients across cell membranes generate a transmembrane voltage that regulates the function of numerous membrane proteins such as ion channels, transporters, pumps and enzymes. The mechanisms by which proteins sense voltage is diverse: ion channels have a conserved, positively charged transmembrane region that moves in response to changes in membrane potential, some G-protein coupled receptors possess a specific voltage-sensing motif and some membrane pumps and transporters use the ions that they transport across membranes to sense membrane voltage. Characterizing the general features of voltage sensors might lead to the discovery of further membrane proteins that are voltage regulated.
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References
Armstrong, C. M. & Bezanilla, F. Currents related to movement of the gating particles of the sodium channels. Nature 242, 459–461 (1973).
Conti, F. & Stuhmer, W. Quantal charge redistribution accompanying the structural transitions of sodium channels. Eur. Biophys. J. 17, 53–59 (1989).
Sigg, D., Stefani, E. & Bezanilla, F. Gating current noise produced by elementary transition in shaker potassium channels. Science 264, 578–582 (1994).
Sigg, D., Bezanilla, F. & Stefani, E. Fast gating in the Shaker K+ channel and the energy landscape of activation. Proc. Natl Acad. Sci. USA 100, 7611–7615 (2003).
Armstrong, C. M. & Bezanilla, F. Inactivation of the sodium channel. II. Gating current experiments. J. Gen. Physiol. 70, 567–590 (1977).
Miller, C. ClC chloride channels viewed through a transporter lens. Nature 440, 484–489 (2006).
Chen, M.-F. & Chen, T.-Y. Side-chain charge effects and conductance determinants in the pore of ClC-0 chloride channels. J. Gen. Physiol. 122, 133–145 (2003).
Schoppa, N. E., McCormack, K., Tanouye, M. A. & Sigworth, F. J. The size of gating charge in wild-type and mutant shaker potassium channels. Science 255, 1712–1715 (1992).
Seoh, S.-A., Sigg, D., Papazian, D. M. & Bezanilla, F. Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron 16, 1159–1167 (1996).
Noda, M. et al. Primary structure of electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312, 121–127 (1984).
Aggarwal, S. K. & MacKinnon, R. Contribution of the S4 segment to gating charge in the Shaker K+ channel. Neuron 16, 1169–1177 (1996).
Catterall, W. A. Molecular properties of voltage-sensitive sodium channels Annu. Rev. Biochem. 55, 953–985 (1986).
Guy, H. R. & Seetharamulu, P. Molecular model of the action potential sodium channel. Proc. Natl Acad. Sci. USA 83, 508–512 (1986).
Jiang, Y., Ruta, V., Chen, J., Lee, A. & MacKinnon, R. The principle of gating charge movement in a voltage-dependent K+ channel. Nature 423, 42–48 (2003).
Bezanilla, F. The voltage sensor in voltage-dependent ion channels. Physiol. Rev. 80, 555–592 (2000). A review of the biophysical properties of voltage-dependent channels.
Tombola, F., Pathak, M. M. & Isacoff, E. Y. How does voltage open an ion channel? Annu. Rev. Cell Dev. Biol. 22, 23–52 (2006).
Starace, D. M. & Bezanilla, F. A proton pore in a potassium channel voltage sensor reveals a focused electric field. Nature 427, 548–552 (2004).
Tombola, F., Pathak, M. M. & Isacoff, E. Y. Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron 45, 379–388 (2005).
Tombola, F, Pathak, M. M., Gorostiza, P. & Isacoff, E. Y. The twisted ion-permeation pathway of a resting voltage-sensing domain. Nature 445, 546–549 (2007).
Ahern, C. A. & Horn, R. Focused electric field across the voltage sensor of potassium channels. Neuron 48, 25–29 (2005).
Long, S. B., Campbell, E. B. & MacKinnon, R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309, 897–903 (2005). Crystal structure of a voltage-gated channel.
Jogini, V. & Roux, B. Dynamics of the Kv1.2 voltage-gated K+ channel in a membrane environment. Biophys. J. 93, 3070–3082 (2007).
Asamoah, O. K., Wuskell, J. P., Loew, L. M. & Bezanilla, F. A fluorometric approach to local electric field measurements in a voltage-gated ion channel. Neuron 37, 85–97 (2003).
Chanda, B., Asamoah, O. K., Blunck, R., Roux, B. & Bezanilla, F. Gating charge displacement in voltage-gated channels involves limited transmembrane movement. Nature 436, 852–856 (2005).
Posson, D. J., Ge, P., Miller, C., Bezanilla, F. & Selvin, P. R. Small vertical movement of a K+ channel voltage sensor measured with luminescence energy transfer. Nature 436, 848–851 (2005).
Ruta, V., Chen, J. & MacKinnon, R. Calibrated measurement of gating-charge arginine displacement in the KvAP voltage-dependent K+ channel. Cell 123, 463–475 (2005).
Yarov-Yarovoy, V., Baker, D. & Catterall, W. A. Voltage sensor conformations in the open and closed states in ROSETTA structural models of K+ channels. Proc. Natl Acad. Sci. USA 103, 7292–7297 (2006).
Pathak, M. M. et al. Closing in on the resting state of the Shaker K+ channel. Neuron 56, 124–140 (2007).
Campos, F. V., Chanda, B., Roux, B. & Bezanilla, F. Two atomic constraints unambiguously position the S4 segment relative to S1 and S2 segments in the closed state of Shaker K channel. Proc. Natl Acad. Sci. USA 104, 7904–7909 (2007).
Long, S. B., Tao, X. Campbell, E. B. & MacKinnon, R. Atomic structure of a voltage-dependent K channel in a lipid membrane-like environment. Nature 450, 376–383 (2007).
Webster, S. M., Del Camino, D., Dekker, J. P. & Yellen, G. Intracellular gate opening in Shaker K+ channels defined by high-affinity metal bridges. Nature 428, 864–868 (2004).
Noceti, F. et al. Effective gating charges per channel in voltage-dependent K+ and Ca2+ channel. J. Gen. Physiol. 108, 143–155 (1996).
Hirschberg, B., Rovner, A., Lieberman, M. & Patlak, J. Transfer of twelve charges is needed to open skeletal muscle Na+ channels. J. Gen. Physiol. 106, 1053–1068 (1996).
Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952). The first description of voltage-dependent conductance.
Chanda, B. & Bezanilla, F. Tracking voltage-dependent conformational changes in skeletal muscle sodium channel during activation. J. Gen. Physiol. 120, 629–645 (2002).
Chanda, B., Asamoah, O. K & Bezanilla, F. Coupling interactions between voltage sensors of the sodium channel as revealed by site-specific measurements. J. Gen. Physiol. 123, 217–230 (2004).
Campos, F. V, Chanda, B., Beirao, P. S. L. & Bezanilla, F. β-Scorpion toxin modifies gating transitions in all four voltage sensors of the sodium channel. J. Gen. Physiol. 130, 257–268 (2007).
Horn, R., Ding, S. & Gruber, H. J. Immobilizing the moving parts of voltage-gated ion channels. J. Gen. Physiol. 116, 461–476 (2000).
Mannuzzu, L. M. & Isacoff, E. Y. Independence and cooperativity in rearrangements of a potassium channel voltage sensor revealed by single subunit fluorescence. J. Gen. Physiol. 115, 257–268 (2000).
Aldrich, R. W., Corey, D. P. & Stevens, C. F. A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature 306, 436–441 (1983).
Sheets, M. F. & Hanck, D. A. Gating of skeletal and cardiac muscle sodium channels in mammalian cells. J. Physiol. 514, 425–436 (1999).
West, J. W. et al. A cluster of hydrophobic amino acid residues required for fast Na+-channels inactivation. Proc. Natl Acad. Sci. USA 89, 10910–10914 (1992).
Cha, A., Ruben, P. C., George, A. L., Fujimoto, E. & Bezanilla, F. Voltage sensors in domains III and IV, but not I and II, are immobilized by Na+ channel fast inactivation. Neuron 22, 73–87 (1999).
Sasaki, M., Takagi, M. & Okamura, Y. A voltage sensor-domain protein is a voltage-gated proton channel. Science 312, 589–592 (2006).
Ramsey, S., Moran, M. M., Chong, J. A., Clapham, D. E. A voltage-gated proton-selective channel lacking the pore domain. Nature 440, 1213–1216 (2006).
Latorre, R. et al. Molecular coupling between voltage sensor and pore opening in the arabidopsis inward rectifier K channel KAT1. J. Gen. Physiol. 122, 459–469 (2003).
Mãnnikkõ, R., Elinder, F. & Larsson, H. P. Voltage sensing mechanism is conserved among ion channels gated by opposite voltages. Nature 419, 837–841 (2002).
Smith, P., Braukowitz, T. & Yellen, G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379, 833–836 (1996).
Murata, M., Iwasaki, H., Sasaki, M., Inaba, K. & Okamura, Y. Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature 435, 1239–1243 (2005). The description of the voltage-dependent phosphatase.
Murata, Y. & Okamura, Y. Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2. J. Physiol. 583, 875–889 (2007).
Gether, U. Uncovering molecular mechanisms involved in activation of G protein- coupled receptors. Endocrinol. Rev. 21, 90–113 (2000).
Ben-Chain, Y. et al. Movement of 'gating charge' is coupled to ligand binding in a G-protein coupled receptor. Nature 444, 106–109 (2006).
Ben-Chaim, Y., Tour, O., Dascal, N., Parnas, I. & Parnas, H. The M2 muscarinic G-protein-coupled receptor is voltage-sensitive. J. Biol. Chem. 278, 22482–22491 (2003).
Parent, L., Suplisson, S., Loo, D. D. F. & Wright, E. M. Electrogenic properties of the cloned Na+/glucose cotransporter: II. A transport model under nonrapid equilibrium conditions. J. Membr. Biol. 130, 203 (1992).
Loo, D. F. et al. Conformational changes couple Na+ and glucose transport. Proc. Natl Acad. Sci. USA 95, 7789–7794.
Loo, D. F., Hirayama, B. A., Cha, A., Bezanilla, F. & Wright, E. M. Perturbation analysis of the voltage-sensitive conformational changes of the Na+/glucose cotransporter. J. Gen. Physiol. 125, 13–36 (2005).
Zampighi, G. A. et al. A method for determining the unitary functional capacity of cloned channels and transporters expressed in Xenopus laevis oocytes. J. Membr. Biol. 148, 65–78 (1995).
Abramson, J. et al. Structure and mechanism of the lactose permease of Escherichia coli. Science 301, 610–615 (2003).
Nakao, M. & Gadsby, D. C. Voltage dependence of Na translocation by the Na/K pump. Nature 323, 628–630 (1986).
Holmgren, M. et al. Three distinct and sequential steps in the release of sodium ions by the Na+/K+ ATPase. Nature 403, 898–901 (2000).
Morth, J. P. et al. Crystal structure of the sodium-potassium pump. Nature 450, 1043–1049 (2007).
Bezanilla, F. in Cell Membrane Transport Ch. 3 (eds Yudilevich, D. L., Deves, R, Peran, S. & Cabantchik, Z. I.) 39–56 (Plenum Press, New York, 1991).
Acknowledgements
Many thanks to Walter Sandtner and Benoit Roux for comments. F.B. is supported by a National Institutes of Health grant.
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Glossary
- Electrochemical gradient
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The electrical and chemical driving force that moves ions.
- Membrane potential
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The difference between the internal minus the external potential in a membrane.
- Dielectric
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An insulator or substance of very low electrical conductivity.
- Capacitor
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A device that can store electrical charge.
- Electric field
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The space that surrounds an electric charge. For a stationary charge, the electric field E at the position where a particle of charge q is located is defined by the vector E = F/q, where F is the force exerted on the particle.
- Electric dipole
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Two opposite charges of the same magnitude that are separated by a finite distance.
- Gating current
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The transient electric current that is produced by the movement of the gating charges.
- Sensing currents
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A more general term for gating currents.
- Voltage clamp
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An electronic device that imposes a defined potential difference across the membrane.
- Q-V curve
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A plot of the voltage dependence of the gating charge.
- Capacitive current
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The current that flows into and out of the plates of the capacitor during its charge or discharge.
- Inactivation
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The process of conductance reduction during maintained depolarization.
- HERG potassium channel
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This is the human ether-a-go-go related channel, which is a potassium channel that is classified as Kv11.1.
- PTEN
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A phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate to obtain phosphatidylinositol (4,5)-bisphosphate.
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Bezanilla, F. How membrane proteins sense voltage. Nat Rev Mol Cell Biol 9, 323–332 (2008). https://doi.org/10.1038/nrm2376
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DOI: https://doi.org/10.1038/nrm2376
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