Evolutionary determinants of divergent calcium selectivity of TRPM channels

FASEB J. 2008 May;22(5):1540-51. doi: 10.1096/fj.07-9694com. Epub 2007 Dec 11.


The mammalian TRPM gene family can be subdivided into distinct categories of cation channels that are either highly permeable for Ca(2+) (TRPM3/6/7), nonselective (TRPM2/8), or even Ca(2+) impermeable (TRPM4/5). TRPM6/7 are fused to alpha-kinase domains, whereas TRPM2 is linked to an ADP-ribose phosphohydrolase (Nudix domain). At a molecular level, the evolutionary steps that gave rise to the structural and functional TRPM channel diversity remain elusive. Here, we provide phylogenetic evidence that Nudix-linked channels represent an ancestral type of TRPMs that is present in various phyla, ranging from protists to humans. Surprisingly, the pore-forming segments of invertebrate TRPM2-like proteins display high sequence similarity to those of Ca(2+)-selective TRPMs, while human TRPM2 is characterized by a loss of several conserved residues. Using the patch-clamp technique, Ca(2+) imaging, and site-directed mutagenesis, we demonstrate that restoration of only two "ancient" pore residues in human TRPM2 (Q981E/P983Y) significantly increased (approximately 4-fold) its permeability for Ca(2+). Conversely, introduction of a "modern" sequence motif into mouse TRPM7 (E1047Q/Y1049P) resulted in the loss of Ca(2+) permeation and a linear TRPM2-like current-voltage relationship. Overall, our findings provide an integrative view on the evolution of the domain architecture and the structural basis of the distinct ion permeation profiles of TRPM channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism*
  • Evolution, Molecular
  • Humans
  • Magnesium / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Patch-Clamp Techniques
  • Sequence Alignment
  • TRPM Cation Channels / genetics*
  • TRPM Cation Channels / physiology


  • TRPM Cation Channels
  • TRPM2 protein, human
  • Trpm7 protein, mouse
  • Magnesium
  • Calcium