Voltage Sensing in Membranes: From Macroscopic Currents to Molecular Motions

J Membr Biol. 2015 Jun;248(3):419-30. doi: 10.1007/s00232-015-9805-x. Epub 2015 May 14.


Voltage-sensing domains (VSDs) are integral membrane protein units that sense changes in membrane electric potential, and through the resulting conformational changes, regulate a specific function. VSDs confer voltage-sensitivity to a large superfamily of membrane proteins that includes voltage-gated Na[Formula: see text], K[Formula: see text], Ca[Formula: see text] ,and H[Formula: see text] selective channels, hyperpolarization-activated cyclic nucleotide-gated channels, and voltage-sensing phosphatases. VSDs consist of four transmembrane segments (termed S1 through S4). Their most salient structural feature is the highly conserved positions for charged residues in their sequences. S4 exhibits at least three conserved triplet repeats composed of one basic residue (mostly arginine) followed by two hydrophobic residues. These S4 basic side chains participate in a state-dependent internal salt-bridge network with at least four acidic residues in S1-S3. The signature of voltage-dependent activation in electrophysiology experiments is a transient current (termed gating or sensing current) upon a change in applied membrane potential as the basic side chains in S4 move across the membrane electric field. Thus, the unique structural features of the VSD architecture allow for competing requirements: maintaining a series of stable transmembrane conformations, while allowing charge motion, as briefly reviewed here.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Membrane / chemistry
  • Cell Membrane / physiology
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ion Channel Gating*
  • Lipid Bilayers / chemistry*
  • Membrane Potentials*
  • Membrane Proteins / chemistry*
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Secondary


  • Lipid Bilayers
  • Membrane Proteins