* 605873

POTASSIUM CHANNEL, SUBFAMILY K, MEMBER 10; KCNK10


Alternative titles; symbols

TWIK-RELATED K+ CHANNEL 2; TREK2


HGNC Approved Gene Symbol: KCNK10

Cytogenetic location: 14q31.3     Genomic coordinates (GRCh38): 14:88,180,108-88,326,912 (from NCBI)


TEXT

Description

Potassium channels are ubiquitous multisubunit membrane proteins that regulate membrane potential in numerous cell types. Bang et al. (2000) reported that KCNK10 belongs to the class of mechanosensitive and fatty acid-stimulated K+ channels.


Cloning and Expression

By database searching with sequences of 2P domain K+ channels, Lesage et al. (2000) identified genomic sequence of a novel member of the tandem-pore K+ channel, KCNK10, which they designated TREK2. Using the sequence to screen a human brain cDNA library, Lesage et al. (2000) cloned a KCNK10 cDNA encoding a deduced 528-amino acid protein with 4 membrane spanning domains (M1 to M4), 2 pore domains (P1 and P2), and an extended loop between M1 and P1. It shares 63% sequence identity with TREK (KCNK2; 603219) and 50 to 60% homology with other members of this potassium channel family. RT-PCR analysis demonstrated high expression in pancreas and kidney and more moderate expression in brain, testis, colon, and small intestine. Northern blot analysis in brain detected 4.0- and 7.5-kb transcripts in cerebellum, occipital lobe, putamen, and thalamus. In vitro transfection studies showed that KCNK10 produces rapidly activating and noninactivating outward rectifier K+ channel currents, which are strongly stimulated by polyunsaturated fatty acids such as arachidonic acids. KCNK10 activity is also stimulated by stretch of the cell membrane, acidification of the intracellular medium, and application of inhalational general anesthetics, and is transiently activated by neuroprotective agents such as riluzole. Since KCNK10 channel activity can be regulated by a variety of neurotransmitter receptors, the authors suggested that it plays a role as a target of neurotransmitter action.

Bang et al. (2000) cloned Trek2 from a rat cerebellum cDNA library. The deduced protein contains 538 amino acids. RT-PCR detected highest expression in cerebellum, spleen, and testis.


Gene Structure

KCNK10 contains 7 exons and has an intron in the sequence encoding the P1 domain that is conserved in many members of the 2P domain K+ channels.

GENE FUNCTION Bang et al. (2000) characterized rat Trek2 following expression in COS-7 cells. They recorded a time-independent and noninactivating K+-selective current that was activated by arachidonic acid and other naturally occurring unsaturated free fatty acids.


Biochemical Features

Crystal Structure

Dong et al. (2015) presented crystal structures of the human TREK2 channel (up to 3.4-angstrom resolution) in 2 conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only 1 of these 2 conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. Dong et al. (2015) concluded that these results provided an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.


Mapping

By sequence similarity to STSs mapped by radiation hybrid analysis, Lesage et al. (2000) localized the KCNK10 gene to chromosome 14q31.


REFERENCES

  1. Bang, H., Kim, Y., Kim, D. TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family. J. Biol. Chem. 275: 17412-17419, 2000. [PubMed: 10747911, related citations] [Full Text]

  2. Dong, Y. Y., Pike, A. C. W., Mackenzie, A., McClenaghan, C., Aryal, P., Dong, L., Quigley, A., Grieben, M., Goubin, S., Mukhopadhyay, S., Ruda, G. F., Clausen, M. V., Cao, L., Brennan, P. E., Burgess-Brown, N. A., Sansom, M. S. P., Tucker, S. J., Carpenter, E. P. K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac. Science 347: 1256-1259, 2015. [PubMed: 25766236, related citations] [Full Text]

  3. Lesage, F., Terrenoire, C., Romey, G., Lazdunski, M. Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J. Biol. Chem. 275: 28398-28405, 2000. [PubMed: 10880510, related citations] [Full Text]


Ada Hamosh - updated : 4/15/2015
Patricia A. Hartz - updated : 8/7/2003
Creation Date:
Yen-Pei C. Chang : 4/24/2001
alopez : 04/16/2015
alopez : 4/15/2015
cwells : 10/30/2003
cwells : 8/7/2003
carol : 4/24/2001
carol : 4/24/2001

* 605873

POTASSIUM CHANNEL, SUBFAMILY K, MEMBER 10; KCNK10


Alternative titles; symbols

TWIK-RELATED K+ CHANNEL 2; TREK2


HGNC Approved Gene Symbol: KCNK10

Cytogenetic location: 14q31.3     Genomic coordinates (GRCh38): 14:88,180,108-88,326,912 (from NCBI)


TEXT

Description

Potassium channels are ubiquitous multisubunit membrane proteins that regulate membrane potential in numerous cell types. Bang et al. (2000) reported that KCNK10 belongs to the class of mechanosensitive and fatty acid-stimulated K+ channels.


Cloning and Expression

By database searching with sequences of 2P domain K+ channels, Lesage et al. (2000) identified genomic sequence of a novel member of the tandem-pore K+ channel, KCNK10, which they designated TREK2. Using the sequence to screen a human brain cDNA library, Lesage et al. (2000) cloned a KCNK10 cDNA encoding a deduced 528-amino acid protein with 4 membrane spanning domains (M1 to M4), 2 pore domains (P1 and P2), and an extended loop between M1 and P1. It shares 63% sequence identity with TREK (KCNK2; 603219) and 50 to 60% homology with other members of this potassium channel family. RT-PCR analysis demonstrated high expression in pancreas and kidney and more moderate expression in brain, testis, colon, and small intestine. Northern blot analysis in brain detected 4.0- and 7.5-kb transcripts in cerebellum, occipital lobe, putamen, and thalamus. In vitro transfection studies showed that KCNK10 produces rapidly activating and noninactivating outward rectifier K+ channel currents, which are strongly stimulated by polyunsaturated fatty acids such as arachidonic acids. KCNK10 activity is also stimulated by stretch of the cell membrane, acidification of the intracellular medium, and application of inhalational general anesthetics, and is transiently activated by neuroprotective agents such as riluzole. Since KCNK10 channel activity can be regulated by a variety of neurotransmitter receptors, the authors suggested that it plays a role as a target of neurotransmitter action.

Bang et al. (2000) cloned Trek2 from a rat cerebellum cDNA library. The deduced protein contains 538 amino acids. RT-PCR detected highest expression in cerebellum, spleen, and testis.


Gene Structure

KCNK10 contains 7 exons and has an intron in the sequence encoding the P1 domain that is conserved in many members of the 2P domain K+ channels.

GENE FUNCTION Bang et al. (2000) characterized rat Trek2 following expression in COS-7 cells. They recorded a time-independent and noninactivating K+-selective current that was activated by arachidonic acid and other naturally occurring unsaturated free fatty acids.


Biochemical Features

Crystal Structure

Dong et al. (2015) presented crystal structures of the human TREK2 channel (up to 3.4-angstrom resolution) in 2 conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only 1 of these 2 conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. Dong et al. (2015) concluded that these results provided an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.


Mapping

By sequence similarity to STSs mapped by radiation hybrid analysis, Lesage et al. (2000) localized the KCNK10 gene to chromosome 14q31.


REFERENCES

  1. Bang, H., Kim, Y., Kim, D. TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family. J. Biol. Chem. 275: 17412-17419, 2000. [PubMed: 10747911] [Full Text: https://doi.org/10.1074/jbc.M000445200]

  2. Dong, Y. Y., Pike, A. C. W., Mackenzie, A., McClenaghan, C., Aryal, P., Dong, L., Quigley, A., Grieben, M., Goubin, S., Mukhopadhyay, S., Ruda, G. F., Clausen, M. V., Cao, L., Brennan, P. E., Burgess-Brown, N. A., Sansom, M. S. P., Tucker, S. J., Carpenter, E. P. K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac. Science 347: 1256-1259, 2015. [PubMed: 25766236] [Full Text: https://doi.org/10.1126/science.1261512]

  3. Lesage, F., Terrenoire, C., Romey, G., Lazdunski, M. Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J. Biol. Chem. 275: 28398-28405, 2000. [PubMed: 10880510] [Full Text: https://doi.org/10.1074/jbc.M002822200]


Contributors:
Ada Hamosh - updated : 4/15/2015
Patricia A. Hartz - updated : 8/7/2003

Creation Date:
Yen-Pei C. Chang : 4/24/2001

Edit History:
alopez : 04/16/2015
alopez : 4/15/2015
cwells : 10/30/2003
cwells : 8/7/2003
carol : 4/24/2001
carol : 4/24/2001