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How membrane proteins sense voltage

Nature Reviews Molecular Cell Biology volume 9, pages 323–332 (2008)Cite this article

Key Points

  • Voltage sensors are structures within a protein that can sense the membrane potential.

  • The movement of the sensing charges, combined with the configuration of the electric field, determines the extent of the conformational change that occurs.

  • Gating currents, or more generally sensing currents, are the transient currents that are produced by the movement of the sensing charges.

  • 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.

  • The Na+ channel is responsible for the upstroke of the nerve impulse and differs from K+ channels; it is faster and has intrinsic cooperativity.

  • 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.

  • Some G-protein coupled receptors are voltage dependent. The membrane potential regulates affinity in the m1 and m2 muscarinic receptors and shows sensing currents.

  • 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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Figure 1: The possible structures of voltage sensors.
Figure 2: The basic architecture of voltage-gated channels.
Figure 3: A model of the two extreme configurations of the Shaker K+ channel.
Figure 4: The architecture of several voltage-dependent proteins.

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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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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, 60637, Illinois, USA

    Francisco Bezanilla

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Simulation programs for voltage-gated ion channels and nerve impulses

Glossary

Electrochemical gradient

The electrical and chemical driving force that moves ions.

Membrane potential

The difference between the internal minus the external potential in a membrane.

Dielectric

An insulator or substance of very low electrical conductivity.

Capacitor

A device that can store electrical charge.

Electric field

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

Two opposite charges of the same magnitude that are separated by a finite distance.

Gating current

The transient electric current that is produced by the movement of the gating charges.

Sensing currents

A more general term for gating currents.

Voltage clamp

An electronic device that imposes a defined potential difference across the membrane.

Q-V curve

A plot of the voltage dependence of the gating charge.

Capacitive current

The current that flows into and out of the plates of the capacitor during its charge or discharge.

Inactivation

The process of conductance reduction during maintained depolarization.

HERG potassium channel

This is the human ether-a-go-go related channel, which is a potassium channel that is classified as Kv11.1.

PTEN

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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