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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • COS Cells
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Size*
  • Chlorocebus aethiops
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Mutation
  • Potassium Channels, Tandem Pore Domain / genetics
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Interference
  • Signal Transduction
  • Substrate Specificity
  • Time Factors
  • Transfection
  • Xenopus laevis


  • KCNK13 protein, human
  • Kcnk13 protein, mouse
  • Potassium Channels, Tandem Pore Domain
  • CASP8 protein, human
  • Caspase 8