Properties of the TRPML3 channel pore and its stable expansion by the varitint-waddler-causing mutation

Hyun Jin Kim, Soichiro Yamaguchi, Qin Li, Insuk So, Shmuel Muallem

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

TRPML3 is a H+-regulated Ca2+ 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 Ca2+ to change its conductance and permeability, which appears to be mediated by trapping Ca2+ 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 Ca2+. 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.

Original languageEnglish (US)
Pages (from-to)16513-16520
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number22
DOIs
StatePublished - May 28 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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