Abstract
Two-pore-domain K+ (K2P) channels sense a wide variety of stimuli such as mechanical stress, inhalational anesthetics, and changes in extracellular pH or temperature. The K2P channel activity forms a background K+ current and, thereby, contributes to resting membrane potentials. Six subfamilies including fifteen subtypes of K2P channels have been identified. Each K2P channel molecule with two pores consists of a homodimer of each subtype. In addition, a few heterodimers mainly within the same subfamilies have been found recently. In the present study, the possibility of heterodimerization between TASK1 (TWIK-Related Acid-Sensitive K+ channel) and TALK2 (TWIK-Related Alkaline pH-Activated K+ channel) was examined. These channels belong to separate subfamilies and show extremely different channel properties. Surprisingly, single molecular imaging analyses in this study using a total internal reflection microscope suggested the heterodimerization of TASK1 and TALK2 in a pancreatic cell line, QGP-1. This heterodimer was also detected using a bimolecular fluorescence complementation assay in a HEK293 heterologous expression system. Fluorescence resonance energy transfer analyses showed that the affinity between TASK1 and TALK2 appeared to be close to those of homodimers. Whole-cell patch-clamp recordings revealed that TASK1 currents in HEK293 cells were significantly attenuated by co-expression of a dominant-negative form of TALK2 in comparison with that of wild-type TALK2. The sensitivities of TASK1-TALK2 tandem constructs to extracellular pH and halothane were characterized as a unique hybrid of TASK1 and TALK2. These results suggested that heterodimerization of TASK1 and TALK2 provides cells with the ability to make multiple responses to a variety of physiological and pharmacological stimuli.
Highlights
Some types of K+ channels play obligatory roles in the formation of resting membrane potentials by pulling it to the direction of the K+ equilibrium potential
MRNA expression of TASK1 and TALK2 in human tissues and pancreatic cell line QGP1 was determined by reverse transcriptionpolymerase chain reaction (RT-PCR)
Co-localization of these channels was clearly detected. These results suggested that TASK1 and TALK2 are expressed and thought to make heterodimers in human tissues
Summary
Some types of K+ channels play obligatory roles in the formation of resting membrane potentials by pulling it to the direction of the K+ equilibrium potential. It has been reported extensively that two-pore-domain K+ (K2P) channels provide background currents in various tissues, such as neurons [1], heart [2], vascular smooth muscle [3], and pancreas [4, 5]. Nakatomi Foundation [https://www.nakatomi.or.jp/ en/index.html] (to Y.S.) and The Uehara Memorial Foundation [http://www.ueharazaidan.or.jp/] The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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