# KCNK2

## Overview
KCNK2 is a gene that encodes the potassium two-pore domain channel subfamily K member 2, commonly referred to as TREK-1. This protein is a member of the two-pore domain potassium (K2P) channel family, which is characterized by its unique structural configuration, including four transmembrane domains and two pore-forming loops per subunit. TREK-1 functions as a transmembrane channel that plays a critical role in maintaining the resting membrane potential and regulating neuronal excitability. It is highly expressed in the central nervous system and is involved in various physiological processes, including responses to mechanical, thermal, and chemical stimuli. The channel's activity is modulated by phosphorylation, which allows it to switch between a potassium-selective leak channel and a voltage-dependent channel, thereby influencing neuronal excitability and neurotransmitter release. KCNK2 has significant clinical implications, with its altered expression and mutations being associated with cardiac arrhythmias, psychiatric disorders, and certain cancers (Unknownauthors2021PathophysiologicalRoleofK2PChannelsinHumanDiseases; Honoré2007The; Bockenhauer2001KCNK2:; Goldstein2001Potassium).

## Structure
KCNK2, also known as TREK-1, is a member of the two-pore domain potassium (K2P) channel family. The protein is characterized by its unique structure, which includes four transmembrane domains and two pore-forming loops per subunit (Plant2023TwoPoreDomain). KCNK2 channels function as dimers, forming a functional channel with a helical cap structure that bifurcates the entry to the potassium conduction pathway (Plant2023TwoPoreDomain). This cap-domain is positioned above the outer mouth of the pore, contributing to the channel's resistance to pore-blocking peptide neurotoxins (Plant2023TwoPoreDomain).

The channel's activity is modulated by post-translational modifications, including phosphorylation. Specifically, the phosphorylation state of a protein kinase A (PKA) consensus site influences the channel's behavior, allowing it to switch from a leak to a voltage-dependent phenotype (Goldstein2001Potassium). This dynamic regulation is crucial for modulating neuronal excitability and facilitating recovery and repetitive firing (Goldstein2001Potassium). Additionally, alternative translation initiation leads to a variant known as K2P2∆, which affects ion permeability and contributes to the channel's polymodal signal integration (Plant2023TwoPoreDomain).

## Function
The KCNK2 gene encodes the TREK-1 channel, a two-pore domain potassium channel that plays a crucial role in maintaining the resting membrane potential and regulating neuronal excitability in healthy human cells. TREK-1 channels are highly expressed in the central nervous system, particularly in the hippocampus, and are involved in various neural responses to stimuli such as temperature, mechanical stretch, and volatile anesthetics (Talley2001CNS; Bockenhauer2001KCNK2:).

TREK-1 channels can exist in two states: as potassium-selective leak channels and as voltage-dependent channels. This reversible conversion is influenced by phosphorylation, particularly at serine 348, which affects the channel's activity and its response to voltage (Bockenhauer2001KCNK2:). In its leak channel form, TREK-1 helps maintain a hyperpolarized resting membrane potential, suppressing excitability. When phosphorylated, it becomes voltage-dependent, allowing for excitation and rapid recovery (Bockenhauer2001KCNK2:).

TREK-1 is also involved in presynaptic modulation by affecting neurotransmitter release, particularly glutamate, which is crucial for neuroprotection and reducing excitotoxicity (Honoré2007The). The channel's activity is modulated by various stimuli, including mechanical, chemical, and thermal changes, making it a polymodal sensory ion channel (Honoré2007The).

## Clinical Significance
Mutations and altered expression of the KCNK2 gene, which encodes the TREK-1 potassium channel, have been implicated in various diseases. In cardiac conditions, KCNK2 is associated with cardiac arrhythmias, QT interval prolongation, and sick sinus syndrome. These conditions are linked to the mechanosensitive nature of TREK-1 channels, which can be activated by membrane stretch and mechanical stress. Mutations affecting protein trafficking and interactions with protein partners like POPDC1 and POPDC2 can lead to sick sinus syndrome and AV block (Wiedmann2021TwoPoreDomain).

In psychiatric disorders, genetic variants in KCNK2 have been associated with treatment resistance in major depressive disorders, suggesting a role in psychiatric conditions (Unknownauthors2021PathophysiologicalRoleofK2PChannelsinHumanDiseases). In cancer, KCNK2 expression is altered in various types, including breast, prostate, and hepatocellular carcinoma, with its expression levels varying across these conditions (Unknownauthors2021PathophysiologicalRoleofK2PChannelsinHumanDiseases; Williams2013Altered).

KCNK2 is also linked to overactive lower urinary tract symptoms (LUTS), with specific single nucleotide polymorphisms (SNPs) in the TREK-1 channel associated with this condition. These mutations can affect channel expression, gating, and ion permeability, contributing to the pathophysiology of overactive LUTS (Nedumaran2018Association).

## Interactions
KCNK2, also known as TREK-1, is involved in various protein interactions that modulate its function. It interacts with G protein-coupled receptors (GPCRs), which can modulate its activity through phosphorylation by protein kinases such as PKA and PKC (Nasr2018Identification). This phosphorylation can influence the channel's behavior, switching it from a leak channel to a voltage-dependent channel, thereby affecting neuronal excitability (Goldstein2001Potassium).

KCNK2 also forms heterodimers with other two-pore-domain potassium channels, including KCNK1 (TWIK-1), KCNK4 (TRAAK), and KCNK10 (TREK-2), which can alter its functional properties (Wiedmann2021TwoPoreDomain). The channel's surface targeting and expression are influenced by interactions with POPDC1 and POPDC2 proteins, with mutations in these proteins potentially leading to cardiac conduction disturbances (Wiedmann2021TwoPoreDomain).

Pharmacologically, KCNK2 is inhibited by selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and the peptide spadin, which target the channel and modulate its activity (Nasr2018Identification). These interactions highlight the channel's role in both cardiac and neurological functions, with implications for conditions such as depression and cardiac arrhythmias.


## References


[1. (Unknownauthors2021PathophysiologicalRoleofK2PChannelsinHumanDiseases) Unknown authors. Pathophysiological role of k2p channels in human diseases. Cellular Physiology and Biochemistry, 55(S3):65–86, March 2021. URL: http://dx.doi.org/10.33594/000000338, doi:10.33594/000000338. This article has 15 citations and is from a peer-reviewed journal.](https://doi.org/10.33594/000000338)

[2. (Plant2023TwoPoreDomain) Leigh D. Plant and Steve A.N. Goldstein. Two-Pore-Domain Potassium Channels, pages 151–162. CRC Press, June 2023. URL: http://dx.doi.org/10.1201/9781003096276-10, doi:10.1201/9781003096276-10. This article has 0 citations.](https://doi.org/10.1201/9781003096276-10)

[3. (Honoré2007The) Eric Honoré. The neuronal background k2p channels: focus on trek1. Nature Reviews Neuroscience, 8(4):251–261, April 2007. URL: http://dx.doi.org/10.1038/nrn2117, doi:10.1038/nrn2117. This article has 405 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/nrn2117)

[4. (Goldstein2001Potassium) Steve A. N. Goldstein, Detlef Bockenhauer, Ita O’Kelly, and Noam Zilberberg. Potassium leak channels and the kcnk family of two-p-domain subunits. Nature Reviews Neuroscience, 2(3):175–184, March 2001. URL: http://dx.doi.org/10.1038/35058574, doi:10.1038/35058574. This article has 540 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/35058574)

[5. (Talley2001CNS) Edmund M. Talley, Guillermo Solórzano, Qiubo Lei, Donghee Kim, and Douglas A. Bayliss. Cns distribution of members of the two-pore-domain (kcnk) potassium channel family. The Journal of Neuroscience, 21(19):7491–7505, October 2001. URL: http://dx.doi.org/10.1523/JNEUROSCI.21-19-07491.2001, doi:10.1523/jneurosci.21-19-07491.2001. This article has 650 citations.](https://doi.org/10.1523/JNEUROSCI.21-19-07491.2001)

[6. (Nedumaran2018Association) Balachandar Nedumaran, Ricardo H. Pineda, Pratyaydipta Rudra, Sanghee Lee, and Anna P. Malykhina. Association of genetic polymorphisms in the pore domains of mechano‐gated trek‐1 channel with overactive lower urinary tract symptoms in humans. Neurourology and Urodynamics, 38(1):144–150, October 2018. URL: http://dx.doi.org/10.1002/nau.23862, doi:10.1002/nau.23862. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/nau.23862)

[7. (Nasr2018Identification) Nathalie Nasr, Adèle Faucherre, Marc Borsotto, Catherine Heurteaux, Jean Mazella, Chris Jopling, and Hamid Moha ou Maati. Identification and characterization of two zebrafish twik related potassium channels, kcnk2a and kcnk2b. Scientific Reports, October 2018. URL: http://dx.doi.org/10.1038/s41598-018-33664-9, doi:10.1038/s41598-018-33664-9. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-018-33664-9)

[8. (Wiedmann2021TwoPoreDomain) Felix Wiedmann, Norbert Frey, and Constanze Schmidt. Two-pore-domain potassium (k2p-) channels: cardiac expression patterns and disease-specific remodelling processes. Cells, 10(11):2914, October 2021. URL: http://dx.doi.org/10.3390/cells10112914, doi:10.3390/cells10112914. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells10112914)

[9. (Williams2013Altered) Sarah Williams, Andrew Bateman, and Ita O’Kelly. Altered expression of two-pore domain potassium (k2p) channels in cancer. PLoS ONE, 8(10):e74589, October 2013. URL: http://dx.doi.org/10.1371/journal.pone.0074589, doi:10.1371/journal.pone.0074589. This article has 60 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0074589)

[10. (Bockenhauer2001KCNK2:) Detlef Bockenhauer, Noam Zilberberg, and S. A. N. Goldstein. Kcnk2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nature Neuroscience, 4(5):486–491, May 2001. URL: http://dx.doi.org/10.1038/87434, doi:10.1038/87434. This article has 139 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/87434)