Motoneurons Express Heteromeric TWIK-Related Acid-Sensitive K⁺(TASK) Channels Containing TASK-1 (KCNK3) and TASK-3 (KCNK9) Subunits

Abstract

Background potassium currents carried by the KCNK family of two-pore-domain K ϩ channels are important determinants of resting membrane potential and cellular excitability. TWIK-related acid-sensitive K ϩ 1 (TASK-1, KCNK3) and TASK-3 (KCNK9) are pHsensitive subunits of the KCNK family that are closely related and coexpressed in many brain regions. There is accumulating evidence that these two subunits can form heterodimeric channels, but this evidence remains controversial. In addition, a substantial contribution of heterodimeric TASK channels to native currents has not been unequivocally established. In a heterologous expression system, we verified formation of heterodimeric TASK channels and characterized their properties; TASK-1 and TASK-3 were coimmunoprecipitated from membranes of mammalian cells transfected with the channel subunits, and a dominant negative TASK-1(Y191F) construct strongly diminished TASK-3 currents. Tandem-linked heterodimeric TASK channel constructs displayed a pH sensitivity (pK ϳ7.3) in the physiological range closer to that of TASK-1 (pK ϳ7.5) than TASK-3 (pK ϳ6.8). On the other hand, heteromeric TASK channels were like TASK-3 insofar as they were activated by high concentrations of isoflurane (0.8 mM), whereas TASK-1 channels were inhibited. The pH and isoflurane sensitivities of native TASK-like currents in hypoglossal motoneurons, which strongly express TASK-1 and TASK-3 mRNA, were best represented by TASK heterodimeric channels. Moreover, after blocking homomeric TASK-3 channels with ruthenium red, we found a major component of motoneuronal isoflurane-sensitive TASK-like current that could be attributed to heteromeric TASK channels. Together, these data indicate that TASK-1 and TASK-3 subunits coassociate in functional channels, and heteromeric TASK channels provide a substantial component of background K ϩ current in motoneurons with distinct modulatory properties.

A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes

“…Thus, other unidentified mechanisms must exist for dimerization of K2P channels. This idea is further supported by a previous report showing TASK-1/TASK-3 heterodimer formation in the absence of cysteine residues normally present in the first loop of each channel 42,43 .…”

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

“…KCNK9 is thought to be co‐expressed with KCNK3 in various tissues outside of the lung, including in the central nervous system, heart, and adrenal glands, and functional heterodimerization of KCNK3 with KCNK9 in multiple tissues has already been studied 6, 11, 12, 13, 175.…”

“…KCNK9, which has been shown to heterodimerize with KCNK3,11 is absent from human lungs of healthy controls and PAH patients (Figure 7A; and see Figure S3D and S3E), but assembles with KCNK3 in tissues where both KCNK9 and KCNK3 are expressed, leading to diversity of channel currents 12, 13, 14. We observed that KCNK9 heterodimerization with WT and G203D KCNK3 increased current activity at physiological pH 7.4 compared with equivalent KCNK3‐only based channels, and suggest that KCNK9 may protect against KCNK3 dysfunction.…”

“…Adding to the complexity of KCNK3 regulation, the closely related acid‐sensitive KCNK9 channel dimerizes with KCNK3, forming KCNK9‐KCNK3 heterodimeric channels in tissues where both channels are expressed 11, 12, 13, 14, 15. KCNK9 is more maximally activated at pH 7.4 than KCNK3 16, 17.…”

TASK-Like Conductances Are Present within Hippocampal CA1 Stratum Oriens Interneuron Subpopulations

“…TASK-1 (KCNK3) and TASK-3 (KCNK9) are the predominant TASK subunit types expressed in the brain (Talley et al, 2001) and exist as homodimers or as TASK-1/TASK-3 heterodimers. TASK-3 homodimers are more sensitive to acidification and less sensitive to alkalization than TASK-1 homodimers or TASK-1/TASK-3 heterodimers (Berg et al, 2004).…”