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Biochim Biophys Acta. 2016 Nov;1863(11):2766-2783. doi: 10.1016/j.bbamcr.2016.08.010. Epub 2016 Aug 23.

Dysregulation of a potassium channel, THIK-1, targeted by caspase-8 accelerates cell shrinkage.

Author information

1
Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan. Electronic address: sakamaki.kazuhiro.7u@kyoto-u.ac.jp.
2
Department of Physiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
3
Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan.
4
Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan.
5
Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan.
6
Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
7
CellFree Sciences Co., Ltd., Yokohama 230-0046, Japan.
8
Proteo-Science Center, Ehime University, Matsuyama 790-8577, Japan.
9
The Institute of Scientific and Industrial Research, Osaka University, Ibaraki 567-0047, Japan.
10
Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
11
Department of Electronic Science and Engineering, Graduate School of Engineering, Kyoto University, Kyoto 615-8530, Japan.
12
Department of Zoology, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
13
SCOTS, Tensei Suisan Co., Ltd., Karatsu 847-0193, Japan.
14
Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
15
Center for Promotion of Excellence in Higher Education, Kyoto University, Kyoto 606-8501, Japan.
16
Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan; The Institute of Scientific and Industrial Research, Osaka University, Ibaraki 567-0047, Japan.

Abstract

Activation of caspases is crucial for the execution of apoptosis. Although the caspase cascade associated with activation of the initiator caspase-8 (CASP8) has been investigated in molecular and biochemical detail, the physiological role of CASP8 is not fully understood. Here, we identified a two-pore domain potassium channel, tandem-pore domain halothane-inhibited K+ channel 1 (THIK-1), as a novel CASP8 substrate. The intracellular region of THIK-1 was cleaved by CASP8 in apoptotic cells. Overexpression of THIK-1, but not its mutant lacking the CASP8-target sequence in the intracellular portion, accelerated cell shrinkage in response to apoptotic stimuli. In contrast, knockdown of endogenous THIK-1 by RNA interference resulted in delayed shrinkage and potassium efflux. Furthermore, a truncated THIK-1 mutant lacking the intracellular region, which mimics the form cleaved by CASP8, led to a decrease of cell volume of cultured cells without apoptotic stimulation and excessively promoted irregular development of Xenopus embryos. Taken together, these results indicate that THIK-1 is involved in the acceleration of cell shrinkage. Thus, we have demonstrated a novel physiological role of CASP8: creating a cascade that advances the cell to the next stage in the apoptotic process.

KEYWORDS:

Apoptosis; Cell shrinkage; FRET; Field effect transistor; Patch clamp; Two-pore potassium channel

PMID:
27566292
DOI:
10.1016/j.bbamcr.2016.08.010
[Indexed for MEDLINE]
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