Role of an N-terminal splice segment in the activation of the cation channel TRPM2 by ADP-ribose and hydrogen peroxide

Neurochem Res. 2009 Feb;34(2):227-33. doi: 10.1007/s11064-008-9755-0. Epub 2008 Jun 3.

Abstract

In the dysfunctional splice variant TRPM2-DeltaN, a stretch of 20 amino acids (aa 537-556) is missing within the N-terminal cytosolic tail of the cation channel TRPM2. The DeltaN-stretch overlaps with two IQ-like calmodulin-binding domains. Moreover, it contains two PxxP motifs implicated in protein-protein interactions. Here, we constructed variants to test whether any of these motifs may explain why TRPM2-DeltaN does not respond to stimulation with either ADP ribose or hydrogen peroxide. Each of the two IQ-motifs could be removed without loss of channel function. Similarly, deletion of either one or both PxxP motifs had no effect. Moreover, the single point mutation D543E associated with bipolar disorder does not change the activation of TRPM2. We conclude that no functional role can be attributed to any of the structural motifs within the DeltaN-stretch that may be a spacer segment for other functional sites in the N terminus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose / pharmacology*
  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Hydrogen Peroxide / pharmacology*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • TRPM Cation Channels / chemistry
  • TRPM Cation Channels / drug effects*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism

Substances

  • TRPM Cation Channels
  • TRPM2 protein, human
  • Adenosine Diphosphate Ribose
  • Hydrogen Peroxide