Functional expression of the epithelial Ca(2+) channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex

EMBO J. 2003 Apr 1;22(7):1478-87. doi: 10.1093/emboj/cdg162.


TRPV5 and TRPV6 constitute the Ca(2+) influx pathway in a variety of epithelial cells. Here, we identified S100A10 as the first auxiliary protein of these epithelial Ca(2+) channels using yeast two-hybrid and GST pull-down assays. This S100 protein forms a heterotetrameric complex with annexin 2 and associates specifically with the conserved sequence VATTV located in the C-terminal tail of TRPV5 and TRPV6. Of these five amino acids, the first threonine plays a crucial role since the corresponding mutants (TRPV5 T599A and TRPV6 T600A) exhibited a diminished capacity to bind S100A10, were redistributed to a subplasma membrane area and did not display channel activity. Using GST pull-down and co-immunoprecipitation assays we demonstrated that annexin 2 is part of the TRPV5-S100A10 complex. Furthermore, the S100A10-annexin 2 pair colocalizes with the Ca(2+) channels in TRPV5-expressing renal tubules and TRPV6-expressing duodenal cells. Importantly, downregulation of annexin 2 using annexin 2-specific small interfering RNA inhibited TRPV5 and TRPV6-mediated currents in transfected HEK293 cells. In conclusion, the S100A10-annexin 2 complex plays a crucial role in routing of TRPV5 and TRPV6 to plasma membrane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A2 / metabolism
  • Base Sequence
  • Calcitriol / metabolism
  • Calcium Channels / metabolism*
  • Calcium-Binding Proteins / metabolism
  • DNA Primers
  • Epithelium / metabolism
  • Gene Silencing
  • Immunohistochemistry
  • Mice
  • Protein Binding
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • S100 Proteins*
  • Two-Hybrid System Techniques


  • Annexin A2
  • Calcium Channels
  • Calcium-Binding Proteins
  • DNA Primers
  • S100 Proteins
  • S100 calcium binding protein A10
  • Calcitriol