The S4---S5 linker - gearbox of TRP channel gating

Cell Calcium. 2017 Nov;67:156-165. doi: 10.1016/j.ceca.2017.04.002. Epub 2017 Apr 4.


Transient receptor potential (TRP) channels are cation channels which participate in a wide variety of physiological processes in organisms ranging from fungi to humans. They fulfill roles in body homeostasis, are sensors for noxious chemicals and temperature in the mammalian somatosensory system and are activated by light stimulated phospholipase C activity in Drosophila or by hypertonicity in yeast. The transmembrane topology of TRP channels is similar to that of voltage-gated cation channels. TRP proteins assemble as tetramers with each subunit containing six transmembrane helices (S1-S6) and intracellular N- and C-termini. Here we focus on the emerging functions of the cytosolic S4-S5 linker on TRP channel gating. Most of this knowledge comes from pathogenic mutations within the S4-S5 linker that alter TRP channel activities. This knowledge has stimulated forward genetic approaches to identify additional residues around this region which are essential for channel gating and is supported, in part, by recent structures obtained for TRPV1, TRPV2, TRPV6, TRPA1, and TRPP2.

Keywords: Channel conformation; Gain-of-function; Gating elements; S4-S5 linker; TRP channelopathies; Transient receptor potential channel.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Channelopathies / classification
  • Channelopathies / genetics*
  • Channelopathies / metabolism
  • Channelopathies / pathology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Gene Expression
  • Humans
  • Ion Channel Gating / genetics*
  • Kinetics
  • Membrane Potentials / physiology
  • Models, Molecular
  • Mutation*
  • Protein Conformation, alpha-Helical
  • Protein Multimerization
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Sequence Homology, Amino Acid
  • Transient Receptor Potential Channels / chemistry*
  • Transient Receptor Potential Channels / genetics
  • Transient Receptor Potential Channels / metabolism


  • Transient Receptor Potential Channels