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KNa1.1

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Target not currently curated in GtoImmuPdb

Target id: 385

Nomenclature: KNa1.1

Family: Calcium- and sodium-activated potassium channels (KCa, KNa)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 0 1230 9q34.3 KCNT1 potassium sodium-activated channel subfamily T member 1 38
Mouse 6 0 1224 2 A3 Kcnt1 potassium channel, subfamily T, member 1 31,34,38
Rat 6 0 1237 3p13 Kcnt1 potassium sodium-activated channel subfamily T member 1 17,21
Previous and Unofficial Names Click here for help
Slo2.2 | KCa4.1 | Slack | potassium channel, sodium activated subfamily T, member 1 | potassium channel, sodium-activated subfamily T, member 1 | potassium channel
Database Links Click here for help
Alphafold Q5JUK3 (Hs), Q6ZPR4 (Mm), Q9Z258 (Rn)
ChEMBL Target CHEMBL4739688 (Hs), CHEMBL4739694 (Mm), CHEMBL4739708 (Rn)
Ensembl Gene ENSG00000107147 (Hs), ENSMUSG00000058740 (Mm), ENSRNOG00000017283 (Rn)
Entrez Gene 57582 (Hs), 227632 (Mm), 60444 (Rn)
Human Protein Atlas ENSG00000107147 (Hs)
KEGG Gene hsa:57582 (Hs), mmu:227632 (Mm), rno:60444 (Rn)
OMIM 608167 (Hs)
Orphanet ORPHA317382 (Hs)
Pharos Q5JUK3 (Hs)
RefSeq Nucleotide NM_020822 (Hs), NM_175462 (Mm), NM_021853 (Rn)
RefSeq Protein NP_065873 (Hs), NP_780671 (Mm), NP_068625 (Rn)
UniProtKB Q5JUK3 (Hs), Q6ZPR4 (Mm), Q9Z258 (Rn)
Wikipedia KCNT1 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
KNa1.2 12
Auxiliary Subunits
Name References
PSD-95 39
Slo1 21
KCa1.1 21
Other Associated Proteins
Name References
FMRP 9,43
TMEM16C 20
Associated Protein Comments
The Slack-B isoform of KNa1.1 forms tetramers with KNa1.2.

FMRP enhances channel opening.

TMEM16C modulates KNa1.2 currents and expression levels.
Functional Characteristics Click here for help
KNa
Ion Selectivity and Conductance Click here for help
Species:  Mouse
Rank order:  K+ > Na+ [5.0 pS]
References:  35,42
Species:  Rat
Rank order:  K+
References:  21
Species:  Rat
Macroscopic current rectification:  Inward
References:  21
Species:  Mouse
Macroscopic current rectification:  Inward
References:  35
Species:  Mouse
Macroscopic current rectification:  Inward
References:  42
Voltage Dependence Comments
Experiment in Xenopus ooctyes showed weak voltage-sensitivity [42]

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
Na+ Click here for species-specific activity table Ligand is endogenous in the given species Rn Agonist - - 1.5x10-2 - 42
⤷ Conc range: 1.5x10-2 M [42]
Cl- Click here for species-specific activity table Ligand is endogenous in the given species Rn Agonist - - 8x10-3 - 42
⤷ Conc range: 8x10-3 M [42]
phorbol 12-myristate 13-acetate Small molecule or natural product Click here for species-specific activity table Rn Agonist 7.0 – 7.3 pEC50 - - 37
⤷ pEC50 7.0 – 7.3 [37]
niclosamide Small molecule or natural product Approved drug Ligand has a PDB structure Hs Agonist 5.5 pEC50 - - 8
⤷ pEC50 5.5 (EC50 2.9x10-6 M) [8]
bithionol Small molecule or natural product Ligand has a PDB structure Rn Agonist 5.0 – 6.0 pEC50 - - 41
⤷ pEC50 5.0 – 6.0 [41]
loxapine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 5.4 pEC50 - - 8
⤷ pEC50 5.4 (EC50 4.4x10-6 M) [8]
View species-specific activator tables
Activator Comments
Cytoplasmic Na+ works synergistically with Cl- for activation
Gating inhibitors Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
Ca2+ Click here for species-specific activity table Ligand is endogenous in the given species Rn Antagonist - - 0x100 - 3x10-6 - 21
⤷ Conc range: 0x100 - 3x10-6 M [21]
Ca2+ Click here for species-specific activity table Mm Antagonist 6.5 pIC50 - - 35
⤷ pIC50 6.5 [35]
bepridil Small molecule or natural product Approved drug Rn - 5.0 – 6.0 pIC50 - - 41
⤷ pIC50 5.0 – 6.0 [41]
View species-specific gating inhibitor tables
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
quinidine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Hs Antagonist - - 1x10-4 - 3x10-4 - 30
⤷ Conc range: 1x10-4 - 3x10-4 M [30]
clofilium Small molecule or natural product Click here for species-specific activity table Hs Antagonist - - 1.09x10-4 - 13
⤷ Conc range: 1.09x10-4 M [13]
quinidine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Rn - 4.0 pIC50 - - 5,41
⤷ pIC50 4.0 [5,41]
tetraethylammonium Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 1.7 – 2.0 pIC50 - - 6
⤷ pIC50 1.7 – 2.0 [6]
View species-specific channel blocker tables
Tissue Distribution Click here for help
Kidney (covering the medullary and cortical thick ascending limbs of Henle’s loop)
Species:  Mouse
Technique:  RT-PCR
References:  35
Brain, Testis, Kidney
Species:  Mouse
Technique:  RT-PCR
References:  4,10,42
Brain:brainstem (red nucleus,oculomotor nucleus, mesencephalic trigeminal, trapezoid nucleus, gigantocellularius, vestibular nucleus), olfactory bulb, frontal cortex, hippocampus. Neuronal immunostaining observed in cell bodies and axonal tracts
Species:  Rat
Technique:  Immunohistochemistry
References:  4
Physiological Functions Click here for help
KCNT1 is proposed to assist apical absorption of Na+ and Cl- in transport epithelium, by providing a basolateral hyperpolarizing potential, linked to increases in intracellular Na+ and Cl-.
Species:  Mouse
Tissue:  Kidney (medullary and cortical thick ascending limbs of Henle’s loop)
References:  35
KCNT1 channels are required for cognitive flexibility and reversal of learning.
Species:  Mouse
Tissue:  CNS
References:  3
KCNT1 channels are proposed to mediate a fast Na+-dependent component of after-hyperpolarizations in MNTB neurons. The decrease in membrane time constant produced by activation of these channels increases the ability of these neurons to follow high frequency stimuli with temporal precision.
Species:  Mouse
Tissue:  Medial nucleus of the trapezoid body (MNTB) in the auditory brainstem
References:  42
KCNT1 channels are proposed to provide a major component of potassium current in several types of central neurons.
Species:  Rat
Tissue:  Medium spiny neuron of the striatum, tufted/mitral cells of olfactory bulb, cortical pyramidal cells
References:  11
KCNT1 channels are proposed to provide a major component of potassium current of olfactory mitral cells in wild type animals and in animals lacking Kv1.3 channels.
Species:  Mouse
Tissue:  Mitral cells in the olfactory bulb
References:  28
KCNT1 channels are proposed to regulate the firing patterns of neurons of the dorsal root ganglion in response to painful stimuli.
Species:  Mouse
Tissue:  Dorsal Root ganglion
References:  27
KCNT1 channels are proposed to regulate the firing patterns of neurons of the dorsal root ganglion in response to painful stimuli.
Species:  Rat
Tissue:  Dorsal Root ganglion
References:  33
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Epilepsy, nocturnal frontal lobe, 5; ENFL5
Synonyms: Autosomal dominant nocturnal frontal lobe epilepsy [Orphanet: ORPHA98784]
OMIM: 615005
Orphanet: ORPHA98784
Disease:  Epileptic encephalopathy, early infantile, 14; EIEE14
Synonyms: Infantile epileptic encephalopathy [Disease Ontology: DOID:2481]
Malignant migrating partial seizures of infancy [Orphanet: ORPHA293181]
Disease Ontology: DOID:2481
OMIM: 614959
Orphanet: ORPHA293181
Disease:  Ohtahara syndrome
Description: A neurological disorder characterized by seizures. The disorder affects newborns, usually within the first three months of life (most often within the first 10 days) in the form of epileptic seizures.
OMIM: 308350
Orphanet: ORPHA1934
Comments:  A KCNT1 mutation has been linked to Ohtahara Syndrome
References:  29
Clinically-Relevant Mutations and Pathophysiology Comments
Additional mutations and information on alterations in KCNT1 function produced by these mutations have been reported [25].
General Comments
KCNT1 and KCNT2 likely encode native KNa channels [1,14,22,42]. Native KNa channels were first recorded from guinea pig cardiac myocytes [23], then later found widely in neurons in the vertebrate central nervous system [15-16,18,26,32,36,40] and dorsal root ganglia [7]. KNa channels have been proposed to protect against hypoxic insult [23], but this and other possible functions remain to be clearly established. Interestingly, C. elegans slo-2 loss-of-function mutants are hypersensitive to hypoxic death [42]. Human mutations in KNa1.1 (KNCT1) give rise to a least three different types of early onset epileptic encephalopathy, each of which has devastating effects on intellectual function [24]. All of the human channel mutations that have been investigated thus far have been found to be associated with several-fold increases in KNa current [2,25,29-30]. The increases in current appear to be caused in major part by enhanced cooperative interactions between individual channels in a cluster [25]. The structure of KNa1.1 channels in the closed state has been resolved by cryo-electron microscopy [19].

References

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1. Anderson NJ, Slough S, Watson WP. (2006) In vivo characterisation of the small-conductance KCa (SK) channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a potential anticonvulsant. Eur J Pharmacol, 546 (1-3): 48-53. [PMID:16925994]

2. Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R et al.. (2012) De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet, 44 (11): 1255-9. [PMID:23086397]

3. Bausch AE, Dieter R, Nann Y, Hausmann M, Meyerdierks N, Kaczmarek LK, Ruth P, Lukowski R. (2015) The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice. Learn Mem, 22 (7): 323-35. [PMID:26077685]

4. Bhattacharjee A, Gan L, Kaczmarek LK. (2002) Localization of the Slack potassium channel in the rat central nervous system. J Comp Neurol, 454 (3): 241-54. [PMID:12442315]

5. Bhattacharjee A, Joiner WJ, Wu M, Yang Y, Sigworth FJ, Kaczmarek LK. (2003) Slick (Slo2.1), a rapidly-gating sodium-activated potassium channel inhibited by ATP. J Neurosci, 23 (37): 11681-91. [PMID:14684870]

6. Bhattacharjee A, Kaczmarek LK. (2005) For K+ channels, Na+ is the new Ca2+. Trends Neurosci, 28 (8): 422-8. [PMID:15979166]

7. Bischoff U, Vogel W, Safronov BV. (1998) Na+-activated K+ channels in small dorsal root ganglion neurones of rat. J Physiol (Lond.), 510 ( Pt 3): 743-54. [PMID:9660890]

8. Biton B, Sethuramanujam S, Picchione KE, Bhattacharjee A, Khessibi N, Chesney F, Lanneau C, Curet O, Avenet P. (2012) The antipsychotic drug loxapine is an opener of the sodium-activated potassium channel slack (Slo2.2). J Pharmacol Exp Ther, 340 (3): 706-15. [PMID:22171093]

9. Brown MR, Kronengold J, Gazula VR, Chen Y, Strumbos JG, Sigworth FJ, Navaratnam D, Kaczmarek LK. (2010) Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci, 13 (7): 819-21. [PMID:20512134]

10. Brown MR, Kronengold J, Gazula VR, Spilianakis CG, Flavell RA, von Hehn CA, Bhattacharjee A, Kaczmarek LK. (2008) Amino-termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation. J Physiol (Lond.), 586 (21): 5161-79. [PMID:18787033]

11. Budelli G, Hage TA, Wei A, Rojas P, Jong YJ, O'Malley K, Salkoff L. (2009) Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology. Nat Neurosci, 12 (6): 745-50. [PMID:19412167]

12. Chen H, Kronengold J, Yan Y, Gazula VR, Brown MR, Ma L, Ferreira G, Yang Y, Bhattacharjee A, Sigworth FJ et al.. (2009) The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels. J Neurosci, 29 (17): 5654-65. [PMID:19403831]

13. de Los Angeles Tejada M, Stolpe K, Meinild AK, Klaerke DA. (2012) Clofilium inhibits Slick and Slack potassium channels. Biologics, 6: 465-70. [PMID:23271893]

14. Dryer SE. (2003) Molecular identification of the Na+-activated K+ channel. Neuron, 37 (5): 727-8. [PMID:12628162]

15. Egan TM, Dagan D, Kupper J, Levitan IB. (1992) Na(+)-activated K+ channels are widely distributed in rat CNS and in Xenopus oocytes. Brain Res, 584 (1-2): 319-21. [PMID:1515948]

16. Egan TM, Dagan D, Kupper J, Levitan IB. (1992) Properties and rundown of sodium-activated potassium channels in rat olfactory bulb neurons. J Neurosci, 12 (5): 1964-76. [PMID:1578280]

17. Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC, Burch PE et al.. (2004) Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature, 428 (6982): 493-521. [PMID:15057822]

18. Hess D, Nanou E, El Manira A. (2007) Characterization of Na+-activated K+ currents in larval lamprey spinal cord neurons. J Neurophysiol, 97 (5): 3484-93. [PMID:17329626]

19. Hite RK, Yuan P, Li Z, Hsuing Y, Walz T, MacKinnon R. (2015) Cryo-electron microscopy structure of the Slo2.2 Na(+)-activated K(+) channel. Nature, 527 (7577): 198-203. [PMID:26436452]

20. Huang F, Wang X, Ostertag EM, Nuwal T, Huang B, Jan YN, Basbaum AI, Jan LY. (2013) TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing. Nat Neurosci, 16 (9): 1284-90. [PMID:23872594]

21. Joiner WJ, Tang MD, Wang LY, Dworetzky SI, Boissard CG, Gan L, Gribkoff VK, Kaczmarek LK. (1998) Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nat Neurosci, 1 (6): 462-9. [PMID:10196543]

22. Kaczmarek LK. (2013) Slack, Slick and Sodium-Activated Potassium Channels. ISRN Neurosci, 2013 (2013). [PMID:24319675]

23. Kameyama M, Kakei M, Sato R, Shibasaki T, Matsuda H, Irisawa H. (1984) Intracellular Na+ activates a K+ channel in mammalian cardiac cells. Nature, 309 (5966): 354-6. [PMID:6328309]

24. Kim GE, Kaczmarek LK. (2014) Emerging role of the KCNT1 Slack channel in intellectual disability. Front Cell Neurosci, 8: 209. [PMID:25120433]

25. Kim GE, Kronengold J, Barcia G, Quraishi IH, Martin HC, Blair E, Taylor JC, Dulac O, Colleaux L, Nabbout R et al.. (2014) Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep, 9 (5): 1661-72. [PMID:25482562]

26. Koh DS, Jonas P, Vogel W. (1994) Na(+)-activated K+ channels localized in the nodal region of myelinated axons of Xenopus. J Physiol (Lond.), 479 ( Pt 2): 183-97. [PMID:7799220]

27. Lu R, Bausch AE, Kallenborn-Gerhardt W, Stoetzer C, Debruin N, Ruth P, Geisslinger G, Leffler A, Lukowski R, Schmidtko A. (2015) Slack channels expressed in sensory neurons control neuropathic pain in mice. J Neurosci, 35 (3): 1125-35. [PMID:25609627]

28. Lu S, Das P, Fadool DA, Kaczmarek LK. (2010) The slack sodium-activated potassium channel provides a major outward current in olfactory neurons of Kv1.3-/- super-smeller mice. J Neurophysiol, 103 (6): 3311-9. [PMID:20393063]

29. Martin HC, Kim GE, Pagnamenta AT, Murakami Y, Carvill GL, Meyer E, Copley RR, Rimmer A, Barcia G, Fleming MR et al.. (2014) Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet, 23 (12): 3200-11. [PMID:24463883]

30. Milligan CJ, Li M, Gazina EV, Heron SE, Nair U, Trager C, Reid CA, Venkat A, Younkin DP, Dlugos DJ et al.. (2014) KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol, 75 (4): 581-90. [PMID:24591078]

31. Mouse Genome Sequencing Consortium, Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M et al.. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature, 420 (6915): 520-62. [PMID:12466850]

32. Nanou E, El Manira A. (2007) A postsynaptic negative feedback mediated by coupling between AMPA receptors and Na+-activated K+ channels in spinal cord neurones. Eur J Neurosci, 25 (2): 445-50. [PMID:17284185]

33. Nuwer MO, Picchione KE, Bhattacharjee A. (2010) PKA-induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability. J Neurosci, 30 (42): 14165-72. [PMID:20962237]

34. Okazaki N, Kikuno R, Ohara R, Inamoto S, Koseki H, Hiraoka S, Saga Y, Nagase T, Ohara O, Koga H. (2003) Prediction of the coding sequences of mouse homologues of KIAA gene: III. the complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries. DNA Res, 10 (4): 167-80. [PMID:14621295]

35. Paulais M, Lachheb S, Teulon J. (2006) A Na+- and Cl- -activated K+ channel in the thick ascending limb of mouse kidney. J Gen Physiol, 127 (2): 205-15. [PMID:16446508]

36. Safronov BV, Vogel W. (1996) Properties and functions of Na(+)-activated K+ channels in the soma of rat motoneurones. J Physiol (Lond.), 497 ( Pt 3): 727-34. [PMID:9003557]

37. Santi CM, Ferreira G, Yang B, Gazula VR, Butler A, Wei A, Kaczmarek LK, Salkoff L. (2006) Opposite regulation of Slick and Slack K+ channels by neuromodulators. J Neurosci, 26 (19): 5059-68. [PMID:16687497]

38. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF et al.. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA, 99 (26): 16899-903. [PMID:12477932]

39. Uchino S, Wada H, Honda S, Hirasawa T, Yanai S, Nakamura Y, Ondo Y, Kohsaka S. (2003) Slo2 sodium-activated K+ channels bind to the PDZ domain of PSD-95. Biochem Biophys Res Commun, 310 (4): 1140-7. [PMID:14559234]

40. Yang B, Desai R, Kaczmarek LK. (2007) Slack and Slick K(Na) channels regulate the accuracy of timing of auditory neurons. J Neurosci, 27 (10): 2617-27. [PMID:17344399]

41. Yang B, Gribkoff VK, Pan J, Damagnez V, Dworetzky SI, Boissard CG, Bhattacharjee A, Yan Y, Sigworth FJ, Kaczmarek LK. (2006) Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology, 51 (4): 896-906. [PMID:16876206]

42. Yuan A, Santi CM, Wei A, Wang ZW, Pollak K, Nonet M, Kaczmarek L, Crowder CM, Salkoff L. (2003) The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron, 37 (5): 765-73. [PMID:12628167]

43. Zhang Y, Brown MR, Hyland C, Chen Y, Kronengold J, Fleming MR, Kohn AB, Moroz LL, Kaczmarek LK. (2012) Regulation of neuronal excitability by interaction of fragile X mental retardation protein with slack potassium channels. J Neurosci, 32 (44): 15318-27. [PMID:23115170]

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