Alternative titles; symbols
HGNC Approved Gene Symbol: KCNK3
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38) : 2:26,692,722-26,733,420 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | Developmental delay with sleep apnea | 621402 | Autosomal dominant | 3 |
| Pulmonary hypertension, primary, 4 | 615344 | Autosomal dominant | 3 |
The KCNK3 gene encodes a pH-sensitive potassium channel in the 4-transmembrane/2-pore domain superfamily. The primary role of KCNK3 channels is to control the resting membrane potential in many cell types, including pulmonary artery smooth muscle cells (summary by Ma et al., 2013). Other members of this family include TWIK (KCNK1; 601745) and TREK (KCNK2; 603219).
Duprat et al. (1997) identified mouse ESTs with similarity to TREK and TWIK and cloned a corresponding cDNA from a mouse brain library. The mouse cDNA was used to clone the human counterpart from a kidney cDNA library. The human cDNA, designated TASK, encodes a 394-amino acid polypeptide with 85% identity to the mouse ortholog. The sequence contains consensus sites for N-linked glycosylation and for phosphorylation at the C terminus. Northern blot analysis showed that TASK is expressed in a variety of human tissues, with highest levels in pancreas and placenta.
By in situ hybridization, Karschin et al. (2001) detected Kcnk3 and Kcnk9 (605874) expression in rat brain, particularly in neurons likely to be cholinergic, serotonergic, or noradrenergic.
Lesage and Lazdunski (1998) used a radiation hybrid mapping panel to map the human KCNK3 gene to chromosome 2p23 between markers WI13615 and WI11298. By fluorescence in situ hybridization, Manjunath et al. (1999) mapped the KCNK3 gene to chromosome 2p24.1-p23.3 and the mouse homolog to chromosome 5B.
By expression of the TASK cDNA, Duprat et al. (1997) found that the functional protein creates currents that are K(+)-selective, instantaneous, and noninactivating. These currents showed an outward rectification when external K+ was low, but evinced absence of activation and inactivation kinetics as well as voltage independence, characteristics of so-called leak or background conductances. TASK currents were very sensitive to small changes in extracellular pH, suggesting that TASK has a role in cellular responses to changes in extracellular pH.
Using in situ hybridization, Talley et al. (2000) showed that Task1 was highly expressed in motoneurons, including hypoglossal motoneurons (HMs), in rat brain. HMs were depolarized in response to fluctuations in extracellular pH, and the sensitivity of HMs to changes in external pH was indistinguishable from that of rat Task1. Moreover, the pH-sensitive current in HMs had voltage- and time-dependent properties of Task1. The pH-sensitive K+ conductance in HMs was inhibited by neurotransmitters, and a residual, pH-insensitive neurotransmitter current was similar to the characteristics of the residual neurotransmitter current resulting from inhibition of Task1. This neurotransmitter effect was entirely reconstituted by coexpressing Task1 and TRHR (188545) in HEK293 cells. The authors concluded that TASK1 is the resting K+ channel modulated by multiple neurotransmitters in HMs.
By in vitro pull-down and coimmunoprecipitation assays, Girard et al. (2002) found that human p11 (S100A10; 114085) interacted directly with the potassium channel TASK1. The association of TASK1 with p11 required the last 3 C-terminal amino acids of TASK1, ser-ser-val. Using a series of C-terminal TASK1 deletion mutants and chimeras, Girard et al. (2002) demonstrated that the association with p11 was essential for TASK1 trafficking to the plasma membrane. The binding of p11 to TASK1 also masked an endoplasmic reticulum retention signal on TASK1 (lys-arg-arg) that precedes the ser-ser-val sequence.
Olschewski et al. (2006) found that KCNK3 is expressed in human pulmonary artery smooth muscle cells, controls the resting potential, and is hypoxia-sensitive, suggesting that it has a role in the regulation of pulmonary vascular tone. Knockdown of KCNK3 resulted in decreased potassium current and membrane depolarization.
Using inhibitors and manipulation of pH, Inoue et al. (2019) demonstrated that Task1 channels played essential roles for acidity-induced excitation or secretion in mouse adrenal medullary (AM) cells. Deletion of Task1 almost abolished the current response to external acidity in AM cells, whereas deletion of Task3 (KCNK9) had no effect on the current response. AM cells exhibited predominantly Task1-like and little Task3-like immunoreactivity, and Task1/Task3 heteromeric channels were not present in significant amounts in wildtype AM cells or PC12 cells. AM and PC12 cells did not express p11, but exogenous expression of p11 in PC12 cells resulted in formation of Task1/Task3 heteromeric channels. Further analysis showed that p11 inhibited Task1 exit from the ER and, consequently, facilitated Task1/Task3 heteromer formation in the ER. In AM cells, deletion of Task1 resulted in upregulation of Talk2 (KCNK17; 607370), but not Task3, suggesting that Talk2 functionally compensated the Task1 deficit in AM cells. Moreover, Task1 homomeric channels functioned as acidity sensors in AM cells, and this function was facilitated by lack of p11 expression.
Yu et al. (2021) found that ectopic expression of TASK1 protected HEK293T cells against hypoxia/reoxygenation-induced injury. TASK1 expression prevented disruption of mitochondrial membrane potential in cells by reducing the release of cytochrome c from mitochondria under hypoxia and reoxygenation. However, hypoxia and reoxygenation did not alter expression and mitochondrial localization of TASK1.
Rodstrom et al. (2020) presented the x-ray crystal structure of human TASK1 and showed that it contained a lower gate, which they designated the X-gate, created by interaction of the 2 crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure was formed by 6 residues (VLRFMT) beginning at position 243 that were essential for responses to volatile anesthetics, neurotransmitters, and G protein-coupled receptors. Mutations within the X-gate and the surrounding regions markedly affected both channel-open probability and activation of the channel by anesthetics. Structures of TASK1 bound to 2 high-affinity inhibitors showed that both compounds bound below the selectivity filter and were trapped in the vestibule by the X-gate, which explained their low washout rates.
Primary Pulmonary Hypertension 4
In affected members of 3 unrelated families with autosomal dominant primary pulmonary hypertension-4 (PPH4; 615344), Ma et al. (2013) identified heterozygous missense mutations in the KCNK3 gene (603220.0001-603220.0003). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Two of 9 mutation carriers did not have evidence of the disease, indicating incomplete penetrance. Three additional heterozygous KCNK3 mutations (see, e.g., 603220.0004-603220.0005) were subsequently found in 3 unrelated patients with sporadic PPH. Overall, KCNK3 mutations were found in 3 (1.3%) of 230 patients with idiopathic disease and in 3 (3.2%) of 93 probands with familial disease. The age at diagnosis ranged from 8 to 44 years, and both males and females were affected. No patients responded to acute vasodilator challenge. Three patients eventually required lung transplantation, and 3 patients died in their forties. In vitro functional expression studies showed that all of the mutant channels had loss of function at physiologic pH compared to wildtype. In addition, 3 mutants tested showed reduced current density when coexpressed with the wildtype channel, consistent with a loss of function. Application of a phospholipase A2 inhibitor was able to ameliorate the reduction in potassium-channel current caused by some, but not all, of the mutant proteins. Ma et al. (2013) suggested that the mutations caused depolarization of the resting membrane potential, which could lead to pulmonary artery vasoconstriction.
Developmental Delay with Sleep Apnea
In 8 unrelated patients with developmental delay with sleep apnea (DDSA; 621402), Sormann et al. (2022) identified de novo heterozygous mutations in the KCNK3 gene (603220.0006-603220.0011). All of the mutations clustered near the X-gate of the TASK1 channel. Two mutations (L239P, 603220.0010; L241F, 603220.0011) were located in the fourth transmembrane domain helix (M4) of the protein, and 4 mutations (L122V, 603220.0006; L122P, 603220.0007; G129D, 603220.0008; N133S, 603220.0009) were located in the second transmembrane domain helix (M2) of the protein. TASK1 with each mutation was expressed in Xenopus oocytes, and all except L239P resulted in increased whole-cell currents compared to wildtype TASK1. TASK1 with each mutation was coexpressed with TASK3 and all the resultant heterotrimeric TASK1-TASK3 currents were increased compared to wildtype TASK1-TASK3 currents, demonstrating a gain of function for each of the KCNK3 mutations. Furthermore, the N133S and L239P mutations were predicted to impact the X-gate of TASK1 and result in increased frequency of channel openings. Cells expressing mutant TASK1 proteins were resistant to G protein-coupled receptor pathway inhibition, thus amplifying the gain-of-function activity.
The 2 patients (probands 8 and 9) with DDSA reported by Sormann et al. (2022) who had KCNK3 mutations localized to the fourth transmembrane helix of the TASK1 protein had a less severe phenotype compared to the rest of the DDSA cohort who had KCNK3 mutations localized to the second transmembrane helix.
Davies et al. (2008) found that Task1 (KCNK3)/Task3 (KCNK9) double-knockout mice were viable and showed no obvious sensorimotor defects. However, in the adrenal gland, they showed a marked depolarization of zona glomerulosa membrane potential. Although double-knockout mice adjusted urinary sodium excretion and aldosterone production to match sodium intake, they produced more aldosterone than controls across a range of sodium intake, and they failed to suppress aldosterone production in response to dietary sodium loading. Overproduction of aldosterone was not the result of enhanced renin-angiotensin activity. Davies et al. (2008) concluded that Task1/Task3 double-knockout mice exhibit primary hyperaldosteronism.
Kitagawa et al. (2017) found that both Task1 -/- and wildtype mice had age-related increases in right ventricular systolic pressure (RVSP) that correlated with age-related vascular remodeling in male mice, but not in female mice. Male Task1 -/- and wildtype mice exposed to chronic hypoxia demonstrated increased RVSP, which decreased following room air recovery. Wildtype and Task1 -/- male mice also demonstrated vascular remodeling upon exposure to hypoxia that persisted in room air recovery. Histologic analysis of vessel hypertrophy indicated that wildtype and Task1 -/- mice did not develop pulmonary hypertension.
In 4 affected members of a family with autosomal dominant primary pulmonary hypertension-4 (PPH4; 615344), Ma et al. (2013) identified a heterozygous c.608G-A transition in the KCNK3 gene, resulting in a gly203-to-asp (G203D) substitution at a highly conserved residue in the second pore region of the protein, which is critical for the gating function of the potassium channel. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases or in 100 ethnically matched controls. One unaffected family member carried the mutation, indicating incomplete penetrance. In vitro functional expression studies showed that the mutant channel had loss of function at physiologic pH compared to wildtype. In addition, there was reduced current density when coexpressed with the wildtype channel, consistent with a loss of function. Application of a phospholipase A2 inhibitor was not able to ameliorate the reduction in potassium-channel current caused by the mutant protein in vitro.
In 2 members of a family with primary pulmonary hypertension (PPH4; 615344), Ma et al. (2013) identified a heterozygous c.289G-A transition in the KCNK3 gene, resulting in a gly97-to-arg (G97R) substitution at a highly conserved residue in the pore domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. An unaffected family member also carried the mutation, indicating incomplete penetrance.
In a woman with primary pulmonary hypertension (PPH4; 615344), Ma et al. (2013) identified a heterozygous c.661G-C transversion in the KCNK3 gene, resulting in a val221-to-leu (V221L) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the mutant channel had loss of function at physiologic pH compared to wildtype. In addition, there was reduced current density when coexpressed with the wildtype channel, consistent with a loss of function. The patient was diagnosed at age 29 years, underwent lung transplantation at age 33, and died at age 40. Her affected brother died at age 13.
In a 40-year-old man with primary pulmonary hypertension (PPH4; 615344), Ma et al. (2013) identified a heterozygous glu182-to-lys (E182K) substitution at a highly conserved residue in the KCNK3 gene. He was diagnosed at age 25 and underwent lung transplant at age 29. There was no family history of a similar disorder. Application of a phospholipase A2 inhibitor was able to ameliorate the reduction in potassium-channel current caused by the mutation in vitro.
In a 20-year-old man with primary pulmonary hypertension (PPH4; 615344), Ma et al. (2013) identified a heterozygous tyr192-to-cys (Y192C) substitution in the KCNK3 gene. He was diagnosed at age 8 years and underwent lung transplantation at age 15. Lung tissue showed medial hypertrophy of the pulmonary arteries, fibrointimal proliferation, and progressive generalized arterial dilatation with formation of complex plexiform lesions.
In a patient (proband 1) with developmental delay with sleep apnea (DDSA; 621402), Sormann et al. (2022) identified heterozygosity for a c.364C-G transversion (c.364C-G, NM_002246) in the KCNK3 gene, resulting in a leu122-to-val (L122V) substitution. The mutation, which was identified by whole-exome sequencing, occurred de novo. The mutation was located in the second transmembrane domain helix (M2) and clustered near the X-gate of the TASK1 channel.
In a patient (proband 2) with developmental delay with sleep apnea (DDSA; 621402), Sormann et al. (2022) identified heterozygosity for a c.365T-C transition (c.365T-C, NM_002246) in the KCNK3 gene, resulting in a leu122-to-pro (L122P) substitution. The mutation, which was identified by whole-exome sequencing, occurred de novo. The mutation was located in the second transmembrane domain helix (M2) and clustered near the X-gate of the TASK1 channel.
In a patient (proband 4) with developmental delay with sleep apnea (DDSA; 621402), Sormann et al. (2022) identified heterozygosity for a c.386G-A transition (c.386G-A, NM_002246) in the KCNK3 gene, resulting in a gly129-to-asp (G129D) substitution. The mutation, which was identified by whole-exome sequencing, occurred de novo. The mutation was located in the second transmembrane domain helix (M2) and clustered near the X-gate of the TASK1 channel.
In 3 unrelated patients (probands 5, 6, and 7) with developmental delay with sleep apnea (DDSA; 621402), Sormann et al. (2022) identified heterozygosity for a c.398A-G transition (c.398A-G, NM_002246) in the KCNK3 gene, resulting in an asn133-to-ser (N133S) substitution. The mutation, which was identified by whole-exome sequencing, occurred de novo in each patient. The mutation was located in the second transmembrane domain helix (M2) and clustered near the X-gate of the TASK1 channel.
In a patient (proband 8) with developmental delay with sleep apnea (DDSA; 621402), Sormann et al. (2022) identified heterozygosity for a c.716T-C transition (c.716T-C, NM_002246) in the KCNK3 gene, resulting in a leu239-to-pro (L239P) substitution. The mutation, which was identified by whole-exome sequencing, occurred de novo. The mutation was located in the fourth transmembrane domain helix (M4) and clustered near the X-gate of the TASK1 channel.
In a patient (proband 9) with developmental delay with sleep apnea (DDSA; 621402), Sormann et al. (2022) identified heterozygosity for a c.721C-T transition (c.721C-T, NM_002246) in the KCNK3 gene, resulting in a leu241-to-phe (L241F) substitution. The mutation, which was identified by whole-exome sequencing, occurred de novo. The mutation was located in the fourth transmembrane domain helix (M4) and clustered near the X-gate of the TASK1 channel.
Davies, L. A., Hu, C., Guagliardo, N. A., Sen, N., Chen, X., Talley, E. M., Carey, R. M., Bayliss, D. A., Barrett, P. Q. TASK channel deletion in mice causes primary hyperaldosteronism. Proc. Nat. Acad. Sci. 105: 2203-2208, 2008. Note: Erratum: Proc. Nat. Acad. Sci. 105: 13696 only, 2008. [PubMed: 18250325] [Full Text: https://doi.org/10.1073/pnas.0712000105]
Duprat, F., Lesage, F., Fink, M., Reyes, R., Heurteaux, C., Lazdunski, M. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J. 16: 5464-5471, 1997. [PubMed: 9312005] [Full Text: https://doi.org/10.1093/emboj/16.17.5464]
Girard, C., Tinel, N., Terrenoire, C., Romey, G., Lazdunski, M., Borsotto, M. p11, an annexin II subunit, an auxiliary protein associated with the background K(+) channel, TASK-1. EMBO J. 21: 4439-4448, 2002. [PubMed: 12198146] [Full Text: https://doi.org/10.1093/emboj/cdf469]
Inoue, M., Matsuoka, H., Lesage, F., Harada, K. Lack of p11 expression facilitates acidity-sensing function of TASK1 channels in mouse adrenal medullary cells. FASEB J. 33: 455-468, 2019. [PubMed: 30001168] [Full Text: https://doi.org/10.1096/fj.201800407RR]
Karschin, C., Wischmeyer, E., Preisig-Muller, R., Rajan, S., Derst, C., Grzeschik, K.-H., Daut, J., Karschin, A. Expression pattern in brain of TASK-1, TASK-3, and a tandem pore domain K+ channel subunit, TASK-5, associated with the central auditory nervous system. Molec. Cell. Neurosci. 18: 632-648, 2001. [PubMed: 11749039] [Full Text: https://doi.org/10.1006/mcne.2001.1045]
Kitagawa, M. G., Reynolds, J. O., Wehrens, X. H. T., Bryan, R. M., Pandit, L. M. Hemodynamic and pathologic characterization of the TASK-1 -/- mouse does not demonstrate pulmonary hypertension. Front. Med. (Lausanne) 4: 177, 2017. [PubMed: 29109948] [Full Text: https://doi.org/10.3389/fmed.2017.00177]
Lesage, F., Lazdunski, M. Mapping of human potassium channel genes TREK-1 (KCNK2) and TASK (KCNK3) to chromosomes 1q41 and 2p23. Genomics 51: 478-479, 1998. [PubMed: 9721223] [Full Text: https://doi.org/10.1006/geno.1998.5397]
Ma, L., Roman-Campos, D., Austin, E. D., Eyries, M., Sampson, K. S., Soubrier, F., Germain, M., Tregouet, D. A., Borczuk, A., Rosenzweig, E. B., Girerd, B., Montani, D., Humbert, M., Loyd, J. E., Kass, R. S., Chung, W. K. A novel channelopathy in pulmonary arterial hypertension. New Eng. J. Med. 369: 351-361, 2013. [PubMed: 23883380] [Full Text: https://doi.org/10.1056/NEJMoa1211097]
Manjunath, N. A., Bray-Ward, P., Goldstein, S. A. N., Gallagher, P. G. Assignment of the 2P domain, acid-sensitive potassium channel OAT1 gene KCNK3 to human chromosome bands 2p24.1-p23.3 and murine 5B by in situ hybridization. Cytogenet. Cell Genet. 86: 242-243, 1999. [PubMed: 10575216] [Full Text: https://doi.org/10.1159/000015349]
Olschewski, A., Li, Y., Tang, B., Hanze, J., Eul, B., Bohle, R. M., Wilhelm, J., Morty, R. E., Brau, M. E., Weir, E. K., Kwapiszewska, G., Klepetko, W., Seeger, W., Olschewski, H. Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circ. Res. 98: 1072-1080, 2006. [PubMed: 16574908] [Full Text: https://doi.org/10.1161/01.RES.0000219677.12988.e9]
Rodstrom, K. E. J., Kiper, A. K., Zhang, W., Rinne, S., Pike, A. C. W., Goldstein, M., Conrad, L. J., Delbeck, M., Hahn, M. G., Meier, H., Platzk, M., Quigley, A., Speedman, D., Shrestha, L., Mukhopadhyay, S. M. M., Burgess-Brown, N. A., Tucker, S. J., Muller, T., Decher, N., Carpenter, E. P. A lower X-gate in TASK channels traps inhibitors within the vestibule. Nature 582: 443-447, 2020. [PubMed: 32499642] [Full Text: https://doi.org/10.1038/s41586-020-2250-8]
Sormann, J., Schewe, M., Proks, P., Jouen-Tachoire, T., Rao, S., Riel, E. B., Agre, K. E., Begtrup, A., Dean, J., Descartes, M., Fischer, J., Gardham, A., and 18 others. Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea. Nature Genet. 54: 1534-1543, 2022. [PubMed: 36195757] [Full Text: https://doi.org/10.1038/s41588-022-01185-x]
Talley, E. M., Lei, Q., Sirois, J. E., Bayliss, D. A. TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25: 399-410, 2000. [PubMed: 10719894] [Full Text: https://doi.org/10.1016/s0896-6273(00)80903-4]
Yu, Y., He, H., Kang, C., Hu, K. TASK-1 regulates mitochondrial function under hypoxia. Biochem. Biophys. Res. Commun. 578: 163-169, 2021. [PubMed: 34571371] [Full Text: https://doi.org/10.1016/j.bbrc.2021.09.032]