Silent but not dumb: how cellular trafficking and pore gating modulate expression of TWIK1 and THIK2

Description

Among K2P channels, a few of them turned out tobe difficult to express in heterologous systems and werecoined "silent subunits". Recent studies have shed light onthe mechanisms behind this apparent lack of channel activityat the plasma membrane. For TWIK1 and THIK2 channels,silence is related to a combination of intracellular retentionand low intrinsic activity. TWIK1 is constitutivelyendocytosed from the plasma membrane before beingtransported to recycling endosomes, whereas THIK2 is restricted to endoplasmic reticulum. These intracellular localizations are related to trafficking signals located in the cytoplasmic parts of the channels. When these motifs are mutatedor masked, channels are redistributed at the plasma membraneand produce measurable currents. However, these currents areof modest amplitude. This weak basal activity is due to ahydrophobic barrier in the deep pore that limits water andions in the conduction pathway. Other silent channelsKCNK7, TWIK2, and TASK5 are still under study. Expression and characterization of these K2P channels pave the wayfor a better understanding of the mechanisms controllingintracellular trafficking of membrane proteins, ion conduction,and channel gating.

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