| Structural highlights
Disease
KCNJ2_HUMAN Andersen-Tawil syndrome;Familial short QT syndrome;Familial atrial fibrillation. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
KCNJ2_HUMAN Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it (PubMed:36149965, PubMed:7590287, PubMed:9490857). Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages (PubMed:7590287, PubMed:7696590). The inward rectification is mainly due to the blockage of outward current by internal magnesium (PubMed:9490857). Can be blocked by extracellular barium or cesium (PubMed:7590287, PubMed:7696590). Probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues (PubMed:7590287, PubMed:7696590, PubMed:7840300).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Inwardly rectifying potassium (Kir) channels play a pivotal role in physiology by establishing, maintaining, and regulating the resting membrane potential of the cells, particularly contributing to the cellular repolarization of many excitable cells. Dysfunction in Kir2.1 channels is implicated in several chronic and debilitating human diseases for which there are currently no effective treatments. Specifically, Kir2.1-R312H and Kir2.1-C154Y mutations are associated with Andersen-Tawil syndrome (ATS) in humans. We have investigated the impact of these two mutants in the trafficking of the channel to the cell membrane and function in Xenopus laevis oocytes. Despite both mutations being trafficked to the cell membrane at different extents and capable of binding PIP(2) (phosphatidylinositol-4,5-bisphosphate), the main modulator for channel activity, they resulted in defective channels that do not display K(+) current, albeit through different molecular mechanisms. Coexpression studies showed that R312H and C154Y are expressed and associated with the WT subunits. While WT subunits could rescue R312H dysfunction, the presence of a unique C154Y subunit disrupts the function of the entire complex, which is a typical feature of mutations with a dominant-negative effect. Molecular dynamics simulations showed that Kir2.1-C154Y mutation induces a loss in the structural plasticity of the selectivity filter, impairing the K(+) flow. In addition, the cryo-EM structure of the Kir2.1-R312H mutant has been reconstructed. This study identified the molecular mechanisms by which two ATS-causing mutations impact Kir2.1 channel function and provide valuable insights that can guide potential strategies for the development of future therapeutic interventions for ATS.
Biochemical, biophysical, and structural investigations of two mutants (C154Y and R312H) of the human Kir2.1 channel involved in the Andersen-Tawil syndrome.,Zuniga D, Zoumpoulakis A, Veloso RF, Peverini L, Shi S, Pozza A, Kugler V, Bonnete F, Bouceba T, Wagner R, Corringer PJ, Fernandes CAH, Venien-Bryan C FASEB J. 2024 Nov 15;38(21):e70146. doi: 10.1096/fj.202401567R. PMID:39520289[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptácek LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell. 2001 May 18;105(4):511-9. PMID:11371347 doi:10.1016/s0092-8674(01)00342-7
- ↑ Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S, Bosi G, Stramba-Badiale M, Jalife J. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005 Apr 15;96(7):800-7. PMID:15761194 doi:10.1161/01.RES.0000162101.76263.8c
- ↑ Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, Zhou Q, Yang Y, Liu Y, Liu B, Zhu Q, Zhou Y, Lin J, Liang B, Li L, Dong X, Pan Z, Wang R, Wan H, Qiu W, Xu W, Eurlings P, Barhanin J, Chen Y. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005 Jul 15;332(4):1012-9. PMID:15922306 doi:10.1016/j.bbrc.2005.05.054
- ↑ Lu CW, Lin JH, Rajawat YS, Jerng H, Rami TG, Sanchez X, DeFreitas G, Carabello B, DeMayo F, Kearney DL, Miller G, Li H, Pfaffinger PJ, Bowles NE, Khoury DS, Towbin JA. Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome. J Med Genet. 2006 Aug;43(8):653-9. PMID:16571646 doi:10.1136/jmg.2006.040816
- ↑ Bendahhou S, Fournier E, Gallet S, Ménard D, Larroque MM, Barhanin J. Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred. Hum Mol Genet. 2007 Apr 15;16(8):900-6. PMID:17324964 doi:10.1093/hmg/ddm034
- ↑ Fernandes CAH, Zuniga D, Fagnen C, Kugler V, Scala R, Péhau-Arnaudet G, Wagner R, Perahia D, Bendahhou S, Vénien-Bryan C. Cryo-electron microscopy unveils unique structural features of the human Kir2.1 channel. Sci Adv. 2022 Sep 23;8(38):eabq8489. PMID:36149965 doi:10.1126/sciadv.abq8489
- ↑ Wood LS, Tsai TD, Lee KS, Vogeli G. Cloning and functional expression of a human gene, hIRK1, encoding the heart inward rectifier K+-channel. Gene. 1995 Oct 3;163(2):313-7. PMID:7590287 doi:10.1016/0378-1119(95)00244-z
- ↑ Raab-Graham KF, Radeke CM, Vandenberg CA. Molecular cloning and expression of a human heart inward rectifier potassium channel. Neuroreport. 1994 Dec 20;5(18):2501-5. PMID:7696590 doi:10.1097/00001756-199412000-00024
- ↑ Ashen MD, O'Rourke B, Kluge KA, Johns DC, Tomaselli GF. Inward rectifier K+ channel from human heart and brain: cloning and stable expression in a human cell line. Am J Physiol. 1995 Jan;268(1 Pt 2):H506-11. PMID:7840300 doi:10.1152/ajpheart.1995.268.1.H506
- ↑ Tang W, Qin CL, Yang XC. Cloning, localization, and functional expression of a human brain inward rectifier potassium channel (hIRK1). Recept Channels. 1995;3(3):175-83 PMID:8821791
- ↑ Tare M, Prestwich SA, Gordienko DV, Parveen S, Carver JE, Robinson C, Bolton TB. Inwardly rectifying whole cell potassium current in human blood eosinophils. J Physiol. 1998 Jan 15;506 ( Pt 2)(Pt 2):303-18. PMID:9490857 doi:10.1111/j.1469-7793.1998.303bw.x
- ↑ Rae JL, Shepard AR. Inwardly rectifying potassium channels in lens epithelium are from the IRK1 (Kir 2.1) family. Exp Eye Res. 1998 Mar;66(3):347-59. PMID:9533862 doi:10.1006/exer.1997.0432
- ↑ Zuniga D, Zoumpoulakis A, Veloso RF, Peverini L, Shi S, Pozza A, Kugler V, Bonneté F, Bouceba T, Wagner R, Corringer PJ, Fernandes CAH, Vénien-Bryan C. Biochemical, biophysical, and structural investigations of two mutants (C154Y and R312H) of the human Kir2.1 channel involved in the Andersen-Tawil syndrome. FASEB J. 2024 Nov 15;38(21):e70146. PMID:39520289 doi:10.1096/fj.202401567R
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