title: Properties of the TRPML3 channel pore and its stable expansion by the Varitint-Waddler-causing mutation.
abstract: 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.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Insuk
authors.initials: I
authors.lastname: So
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D016296:Mutagenesis; D009154:Mutation; D010539:Permeability; D010641:Phenotype; D011392:Proline / Q000235:genetics; D012964:Sodium / Q000737:chemistry; D050051:Transient Receptor Potential Channels / Q000737:chemistry*
chemical_list: C510642:MCOLN3 protein, human; D050051:Transient Receptor Potential Channels; D011392:Proline; D012964:Sodium; D002118:Calcium