TY - JOUR
T1 - Properties of the TRPML3 channel pore and its stable expansion by the varitint-waddler-causing mutation
AU - Kim, Hyun Jin
AU - Yamaguchi, Soichiro
AU - Li, Qin
AU - So, Insuk
AU - Muallem, Shmuel
PY - 2010/5/28
Y1 - 2010/5/28
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.078204
DO - 10.1074/jbc.M109.078204
M3 - Article
C2 - 20378547
AN - SCOPUS:77952765622
SN - 0021-9258
VL - 285
SP - 16513
EP - 16520
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 22
ER -