Properties of the TRPML3 channel pore and its stable expansion by the Varitint-Waddler-causing mutation

J Biol Chem. 2010 May 28;285(22):16513-20. doi: 10.1074/jbc.M109.078204. Epub 2010 Apr 8.


TRPML3 is a H(+)-regulated Ca(2+) channel that shuttles between intracellular compartments and the plasma membrane. The A419P mutation causes the varitint-waddler phenotype as a result of gain-of-function (GOF). The mechanism by which A419P leads to GOF is not known. Here, we show that the TRPML3 pore is dynamic when conducting Ca(2+) to change its conductance and permeability, which appears to be mediated by trapping Ca(2+) within the pore. The pore properties can be restored by strong depolarization or by conducting Na(+) through the pore. The A419P mutation results in expanded channel pore with altered permeability that limits modulation of the pore by Ca(2+). This effect is specific for the A419P mutation and is not reproduced by other GOF mutations, including A419G, H283A, and proline mutations in the fifth transmembrane domain. These findings describe a novel mode of a transient receptor potential channel behavior and suggest that pore expansion by the A419P mutation may contribute to the varitint-waddler phenotype.

Publication types

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

MeSH terms

  • Calcium / chemistry
  • Calcium / metabolism
  • Cell Line
  • Cell Membrane / metabolism
  • Cloning, Molecular
  • Cytoplasm / metabolism
  • Humans
  • Models, Biological
  • Mutagenesis
  • Mutation*
  • Permeability
  • Phenotype
  • Proline / genetics
  • Sodium / chemistry
  • Transient Receptor Potential Channels / chemistry*


  • MCOLN3 protein, human
  • Transient Receptor Potential Channels
  • Proline
  • Sodium
  • Calcium