SUMOylation Silences Heterodimeric TASK Potassium Channels Containing K2P1 Subunits in Cerebellar Granule Neurons

Plant, Leigh D.; Zúñiga, Leandro; Araki, Dan; Marks, Jeremy D.; Goldstein, Steve A.N.

doi:10.1126/scisignal.2003431

Cited by 72 publications

(144 citation statements)

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“…In contradiction with a previous study (23), we found no interaction between TREK1 and TWIK1 (24% of aa identity). Another study failed to demonstrate TREK1/ TWIK1 interaction by using FRET in CHO cells (31). Finally, it has also been suggested that TWIK1 may interact with TASK1 and TASK3, providing another example of assembly between members of distant subfamilies (TWIK1 sharing less than 22% of aa identity with TASK1 and TASK3) (31).…”

Section: Discussionmentioning

confidence: 99%

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

Blin

Soussia

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The tandem of pore domain in a weak inwardly rectifying K + channel (Twik)-related acid-arachidonic activated K + channel (TRAAK) and Twikrelated K + channels (TREK) 1 and TREK2 are active as homodimers gated by stretch, fatty acids, pH, and G protein-coupled receptors. These two-pore domain potassium (K 2P ) channels are broadly expressed in the nervous system where they control excitability. TREK/TRAAK KO mice display altered phenotypes related to nociception, neuroprotection afforded by polyunsaturated fatty acids, learning and memory, mood control, and sensitivity to general anesthetics. These channels have emerged as promising targets for the development of new classes of anesthetics, analgesics, antidepressants, neuroprotective agents, and drugs against addiction. Here, we show that the TREK1, TREK2, and TRAAK subunits assemble and form active heterodimeric channels with electrophysiological, regulatory, and pharmacological properties different from those of homodimeric channels. Heteromerization occurs between all TREK variants produced by alternative splicing and alternative translation initiation. These results unveil a previously unexpected diversity of K 2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs. + channels (TREK) 1, TREK2, and Twik-related acid-arachidonic activated K + channel (TRAAK) channels produce inhibitory background K + currents (1-3). These channels respond to neuroprotective fatty acids, mechanical stretch, temperature, pH, and neurotransmitters through G proteincoupled receptors (GPCRs) (for a recent review, see ref. 4). TREK1 is activated by volatile anesthetics and plays a role in general anesthesia. These channels have emerged as promising targets for the development of other classes of clinical compounds. TREK1 is activated by opioid receptors and contributes to morphine-induced analgesia, but is not involved in morphine-induced constipation, respiratory depression, and dependence (5). TREK1 openers, acting downstream from opioid receptors, might have strong analgesic effects without adverse effects (6). TRAAK may also be a good target for analgesia: Its activation by angiotensin II receptors is responsible for the painless nature of the early lesions of the necrotizing tropical disease Buruli ulcer (7). Also, activation of TREK1 by GABA B receptors in the hippocampus (8), and inhibition of TREK2 by neurotensin receptors in the entorhinal cortex (9), suggests that specific modulators of these channels might also have beneficial actions against drug abuse, and against learning slow down and memory deficits in Alzheimer's disease. Finally, inhibition of TREK1 by spadin (10), an endogenous peptide, or by the antidepressant fluoxetine (Prozac) (11), pinpoints it as a valuable target for the treatment of depression. TREK/TRAAK channels are broadly expressed in the nervous system (12-15). TREK1 is more specifically expressed in the striatum, TREK2 in the cerebellum, and TRAAK in the thalamus. All...

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Section: Discussionmentioning

confidence: 99%

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

Blin

Soussia

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It was recently reported that TWIK-1 can assemble with TASK-1 or TASK-3, but not with TREK-1, in live Chinese Hamster Ovary cells using the fluorescence resonance energy transfer (FRET) technique, though no detailed molecular mechanism was provided 44 . In this report, TWIK-1 showed no positive FRET signal with TREK-1, which appears to be in direct contrast to our positive finding of a strong BiFC signal (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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TWIK-1 is a member of the two-pore domain K þ (K2P) channel family that plays an essential part in the regulation of resting membrane potential and cellular excitability. The physiological role of TWIK-1 has remained enigmatic because functional expression of TWIK-1 channels is elusive. Here we report that native TWIK-1 forms a functional channel at the plasma membrane of astrocytes. A search for TWIK-1-binding proteins led to the identification of TREK-1, another member of the K2P family. The TWIK-1/TREK-1 heterodimeric channel is formed via a disulphide bridge between residue C69 in TWIK-1 and C93 in TREK-1. Gene silencing demonstrates that surface expression of TWIK-1 and TREK-1 are interdependent. TWIK-1/TREK-1 heterodimers mediate astrocytic passive conductance and cannabinoidinduced glutamate release from astrocytes. Our study sheds new light on the diversity of K2P channels.

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“…Moreover, we found that the enzymes that mature, activate, and conjugate SUMO to the channels reside on the cytosolic face of the plasma membrane in tissue culture cells and neurons (Plant et al, 2010(Plant et al, , 2011(Plant et al, , 2012. Here, seeking evidence for Table 1.…”

Section: The Sumo Pathway Regulates Cgn I Namentioning

confidence: 99%

“…Previously, we demonstrated that SUMO introduced in the recording pipette, or washed past excised inside-out membrane patches, decreased I DR in hippocampal neurons (Plant et al, 2011) and suppressed I Kso in CGN (Plant et al, 2012) due to SUMOylation of their pore-forming channel a-subunits, K V 2.1 and K2P1, respectively. Moreover, we found that the enzymes that mature, activate, and conjugate SUMO to the channels reside on the cytosolic face of the plasma membrane in tissue culture cells and neurons (Plant et al, 2010(Plant et al, , 2011(Plant et al, , 2012.…”

Section: The Sumo Pathway Regulates Cgn I Namentioning

confidence: 99%

“…Present in all eukaryotic cells, the SUMO pathway was recognized to regulate the trafficking and activity of nuclear transcription factors when we discovered it to operate as well at the plasma membrane to regulate neuronal excitability via direct SUMOylation of K + channel a-subunits (Rajan et al, 2005;Plant et al, 2010Plant et al, , 2011Plant et al, , 2012. Here, seeking to determine if the SUMO pathway also regulated sodium channels, we documented SUMOylation of Na V 1.2 channels in CGN and then recognized it to be the basis for acute, hypoxic augmentation of I Na .…”

Section: Introductionmentioning

confidence: 99%

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Sumoylation of Na V 1.2 Channels Mediates the Early Response to Acute Hypoxia in Central Neurons

Plant

Marks

Goldstein

2017

Biophysical Journal

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The mechanism for the earliest response of central neurons to hypoxia-an increase in voltage-gated sodium current (I Na )-has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of Na V 1.2 channels increases I Na . The time-course for SUMOylation of single Na V 1.2 channels at the cell surface and changes in I Na coincide, and both are prevented by mutation of Na V 1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of I Na in hypoxic brain damage, the SUMO pathway and Na V 1.2 are identified as potential targets for neuroprotective interventions.

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SUMOylation Silences Heterodimeric TASK Potassium Channels Containing K2P1 Subunits in Cerebellar Granule Neurons

Cited by 72 publications

References 59 publications

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

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

Sumoylation of Na V 1.2 Channels Mediates the Early Response to Acute Hypoxia in Central Neurons

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SUMOylation Silences Heterodimeric TASK Potassium Channels Containing K2P1 Subunits in Cerebellar Granule Neurons

Cited by 72 publications

References 59 publications

Mixing and matching TREK/TRAAK subunits generate heterodimeric K 2P channels with unique properties

Mixing and matching TREK/TRAAK subunits generate heterodimeric K 2P channels with unique properties

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

Sumoylation of Na V 1.2 Channels Mediates the Early Response to Acute Hypoxia in Central Neurons

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Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties