Alternative titles; symbols
HGNC Approved Gene Symbol: KCNK5
Cytogenetic location: 6p21.2 Genomic coordinates (GRCh38): 6:39,188,971-39,229,475 (from NCBI)
The KCNK5 gene encodes a noninactivating, outwardly rectifying, potassium channel expressed in the kidney and in T cells (summary by Bittner et al., 2010). Potassium channels conduct the flux of potassium ions through the membranes of virtually all living cells and are involved in the control of numerous cellular functions, such as neuronal firing, muscle contraction, volume regulation, and hormone secretion. One class of mammalian potassium channels, which includes TWIK1 (KCNK1; 601745), TREK (KCNK2; 603219), and TASK1 (KCNK3; 603220), is characterized by 2 pore-forming (P) domains and 4 transmembrane segments (Reyes et al., 1998).
By searching sequence databases with the protein sequences of 2P domain potassium channels, Reyes et al. (1998) identified an EST encoding TASK2, a new member of this class. They used the EST to screen a human kidney cDNA library and isolated a full-length TASK2 (GenBank AF084830) cDNA that encodes a deduced 499-amino acid polypeptide with a calculated molecular mass of 55.1 kD. TASK2 has all the hallmarks of a 2P domain potassium channel, but shows only 18 to 22% amino acid identity with other 2P domain potassium channels. COS cells expressing TASK2 displayed noninactivating currents, and the current-voltage relationship was outwardly rectifying. Like TASK1 currents, TASK2 currents were highly sensitive to extracellular pH in the physiologic range. Northern blot analysis of adult human tissues detected a 4-kb TASK2 transcript that was expressed abundantly in kidney and to a lesser extent in the pancreas, liver, placenta, and small intestine. In situ hybridization of human kidney localized TASK2 mRNA to the cortical distal tubules and collecting ducts. Reyes et al. (1998) suggested that TASK2 plays an important role in renal potassium transport.
Reyes et al. (1998) mapped the TASK2 gene to chromosome 6p21 by radiation hybrid mapping.
Bittner et al. (2010) demonstrated that TASK2 is constitutively expressed on human T cells, contributes to the resting membrane potential, is sensitive to clofilium and quinidine, and is upregulated by stimulation of T cells. TASK2 is preferentially expressed on CD4+ T helper and CD8+ cytotoxic T cells. Peripheral CD4+ T cells derived from patients with relapsing-remitting multiple sclerosis (MS; 126200) showed a significant upregulation of TASK2 (2-fold) during relapse compared to those from MS patients with stable disease and to controls. TASK2 expression on peripheral CD8+ T cells was more significantly increased in MS patients with acute relapse (7.6-fold) and in those with stable disease (3.3-fold). CSF-derived and CNS lesion-derived cytotoxic T cells from MS patients showed an even greater increase in TASK2 expression compared to peripheral cells. No increase in TASK2 expression was seen in patients with neuromyelitis optica, another neurologic inflammatory disease believed to be mediated by B cells. Pharmacologic or siRNA-mediated knockdown of TASK2 in T cells reduced proliferation and cytokine production, indicating that TASK2 is a key mediator of T-cell physiology.
Kumar et al. (2015) demonstrated that selective expression of the proton-activated receptor GPR4 (600551) in chemosensory neurons of the mouse retrotrapezoid nucleus (RTN) is required for CO2-stimulated breathing. Genetic deletion of GPR4 disrupted acidosis-based activation of RTN neurons, increased apnea frequency, and blunted ventilatory responses to CO2. Reintroduction of GPR4 into RTN neurons restored CO2-dependent RTN neuronal activation and rescued the ventilatory phenotype. Additional elimination of TASK2, a pH-sensitive K+ channel expressed in RTN neurons, essentially abolished the ventilatory response to CO2. Kumar et al. (2015) concluded that their data identified GPR4 and TASK2 as distinct, parallel, and essential central mediators of respiratory chemosensitivity.
Li et al. (2020) presented cryoelectron microscopy structures of mouse Task2 in lipid nanodiscs in open and closed conformations. They identified 2 gates distinct from previously observed K+ channel gates that were controlled by stimuli on either side of the membrane. Intracellular gating involved lysine protonation on inner helices and the formation of a protein seal between the cytoplasm and the channel. Extracellular gating involved arginine protonation on the channel surface and correlated conformational changes that displaced the filter selective for K+ to render it nonconductive. The results explained how internal and external protons control intracellular and selectivity filter gates to modulate TASK2 activity.
Warth et al. (2004) found that Task2-null mice showed increased perinatal mortality. After weaning, knockout mice thrived and were fertile, but they had reduced body weight and arterial blood pressure compared with wildtype mice. Patch-clamp experiments on wildtype and Task2-knockout renal proximal tubular cells indicated that Task2 channels were activated by the rise in basolateral extracellular pH induced by bicarbonate transport. Inulin clearance measurements showed Task2-null mice had normal NaCl and water excretion. During intravenous bicarbonate perfusion, however, renal Na(+) and water reabsorption capacity was reduced. In conscious Task2-null mice, blood pH, bicarbonate concentration, and systemic base excess were reduced, but urinary pH and bicarbonate concentration were increased. Warth et al. (2004) concluded that Task2-knockout mice exhibited metabolic acidosis caused by renal loss of bicarbonate ion.
Bittner, S., Bobak, N., Herrmann, A. M., Gobel, K., Meuth, P., Hohn, K. G., Stenner, M.-P., Budde, T., Wiendl, H., Meuth, S. G. Upregulation of K(2P)5.1 potassium channels in multiple sclerosis. Ann. Neurol. 68: 58-69, 2010. [PubMed: 20582984] [Full Text: https://doi.org/10.1002/ana.22010]
Kumar, N. N., Velic, A., Soliz, J., Shi, Y., Li, K., Wang, S., Weaver, J. L., Sen, J., Abbott, S. B. G., Lazarenko, R. M., Ludwig, M.-G., Perez-Reyes, E., Mohebbi, N., Bettoni, C., Gassmann, M., Suply, T., Seuwen, K., Guyenet, P. G., Wagner, C. A., Bayliss, D. A. Regulation of breathing by CO2 requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science 348: 1255-1260, 2015. [PubMed: 26068853] [Full Text: https://doi.org/10.1126/science.aaa0922]
Li, B., Rietmeijer, R. A., Brohawn, S. G. Structural basis for pH gating of the two-pore domain K+ channel TASK2. Nature 586: 457-462, 2020. [PubMed: 32999458] [Full Text: https://doi.org/10.1038/s41586-020-2770-2]
Reyes, R., Duprat, F., Lesage, F., Fink, M., Salinas, M., Farman, N., Lazdunski, M. Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney. J. Biol. Chem. 273: 30863-30869, 1998. [PubMed: 9812978] [Full Text: https://doi.org/10.1074/jbc.273.47.30863]
Warth, R., Barriere, H., Meneton, P., Bloch, M., Thomas, J., Tauc, M., Heitzmann, D., Romeo, E., Verrey, F., Mengual, R., Guy, N., Bendahhou, S., Lesage, F., Poujeol, P., Barhanin, J. Proximal renal tubular acidosis in TASK2 K(+) channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. Proc. Nat. Acad. Sci. 101: 8215-8220, 2004. [PubMed: 15141089] [Full Text: https://doi.org/10.1073/pnas.0400081101]