Inactivation of the Kv2.1 Channel Through Electromechanical Coupling

Overview

Journal Nature

Specialty Science

Date 2023 Sep 27

PMID 37758949

Authors

Ana I Fernandez-Marino

Xiao-Feng Tan

Chanhyung Bae

Kate Huffer

Jiansen Jiang

Kenton J Swartz

Affiliations

Soon will be listed here.

Abstract

The Kv2.1 voltage-activated potassium (Kv) channel is a prominent delayed-rectifier Kv channel in the mammalian central nervous system, where its mechanisms of activation and inactivation are critical for regulating intrinsic neuronal excitability. Here we present structures of the Kv2.1 channel in a lipid environment using cryo-electron microscopy to provide a framework for exploring its functional mechanisms and how mutations causing epileptic encephalopathies alter channel activity. By studying a series of disease-causing mutations, we identified one that illuminates a hydrophobic coupling nexus near the internal end of the pore that is critical for inactivation. Both functional and structural studies reveal that inactivation in Kv2.1 results from dynamic alterations in electromechanical coupling to reposition pore-lining S6 helices and close the internal pore. Consideration of these findings along with available structures for other Kv channels, as well as voltage-activated sodium and calcium channels, suggests that related mechanisms of inactivation are conserved in voltage-activated cation channels and likely to be engaged by widely used therapeutics to achieve state-dependent regulation of channel activity.

Citing Articles

Small molecule inhibits KCNQ channels with a non-blocking mechanism.

Li J, Yang Z, Zhang S, Ye Y, He J, Zhang Y Nat Chem Biol. 2025; .

PMID: 39814994 DOI: 10.1038/s41589-024-01834-8.

Plural molecular and cellular mechanisms of pore domain encephalopathy.

Abreo T, Thompson E, Madabushi A, Park K, Soh H, Varghese N Elife. 2025; 13.

PMID: 39761077 PMC: 11703504. DOI: 10.7554/eLife.91204.

Abnormal cytoskeletal remodeling but normal neuronal excitability in a mouse model of the recurrent developmental and epileptic encephalopathy-susceptibility KCNB1-p.R312H variant.

Bortolami A, Forzisi Kathera-Ibarra E, Balatsky A, Dubey M, Amin R, Venkateswaran S Commun Biol. 2024; 7(1):1713.

PMID: 39738805 PMC: 11685548. DOI: 10.1038/s42003-024-07344-6.

Worldwide Sodium Channel Conference, January 31st-February 2nd, 2024, Grindelwald, Switzerland.

Pantazis A, Brackenbury W Bioelectricity. 2024; 6(4):288-291.

PMID: 39712211 PMC: 11656014. DOI: 10.1089/bioe.2024.0025.

A novel loss-of-function gene variant in a twin with global developmental delay and seizures.

Manville R, Illeck C, Santos C, Sidlow R, Abbott G Front Cell Neurosci. 2024; 18:1477989.

PMID: 39469306 PMC: 11513283. DOI: 10.3389/fncel.2024.1477989.

References

Misonou H, Mohapatra D, Trimmer J . Kv2.1: a voltage-gated k+ channel critical to dynamic control of neuronal excitability. Neurotoxicology. 2005; 26(5):743-52. DOI: 10.1016/j.neuro.2005.02.003. View

Liu P, Bean B . Kv2 channel regulation of action potential repolarization and firing patterns in superior cervical ganglion neurons and hippocampal CA1 pyramidal neurons. J Neurosci. 2014; 34(14):4991-5002. PMC: 3972724. DOI: 10.1523/JNEUROSCI.1925-13.2014. View

Thiffault I, Speca D, Austin D, Cobb M, Eum K, Safina N . A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. J Gen Physiol. 2015; 146(5):399-410. PMC: 4621747. DOI: 10.1085/jgp.201511444. View

Torkamani A, Bersell K, Jorge B, Bjork Jr R, Friedman J, Bloss C . De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol. 2014; 76(4):529-540. PMC: 4192091. DOI: 10.1002/ana.24263. View

Kang S, Vanoye C, Misra S, Echevarria D, Calhoun J, OConnor J . Spectrum of K 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders. Ann Neurol. 2019; 86(6):899-912. PMC: 7025436. DOI: 10.1002/ana.25607. View

Marini C, Romoli M, Parrini E, Costa C, Mei D, Mari F . Clinical features and outcome of 6 new patients carrying de novo gene mutations. Neurol Genet. 2017; 3(6):e206. PMC: 5733250. DOI: 10.1212/NXG.0000000000000206. View

de Kovel C, Syrbe S, Brilstra E, Verbeek N, Kerr B, Dubbs H . Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA Neurol. 2017; 74(10):1228-1236. PMC: 5710242. DOI: 10.1001/jamaneurol.2017.1714. View

Jan L, Jan Y . Voltage-gated potassium channels and the diversity of electrical signalling. J Physiol. 2012; 590(11):2591-9. PMC: 3424718. DOI: 10.1113/jphysiol.2011.224212. View

Long S, Campbell E, MacKinnon R . Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science. 2005; 309(5736):903-8. DOI: 10.1126/science.1116270. View

10.

Long S, Tao X, Campbell E, MacKinnon R . Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature. 2007; 450(7168):376-82. DOI: 10.1038/nature06265. View

11.

Tan X, Bae C, Stix R, Fernandez-Marino A, Huffer K, Chang T . Structure of the Shaker Kv channel and mechanism of slow C-type inactivation. Sci Adv. 2022; 8(11):eabm7814. PMC: 8932672. DOI: 10.1126/sciadv.abm7814. View

12.

Chi G, Liang Q, Sridhar A, Cowgill J, Sader K, Radjainia M . Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain. Nat Commun. 2022; 13(1):4087. PMC: 9287412. DOI: 10.1038/s41467-022-29594-w. View

13.

Ye W, Zhao H, Dai Y, Wang Y, Lo Y, Jan L . Activation and closed-state inactivation mechanisms of the human voltage-gated K4 channel complexes. Mol Cell. 2022; 82(13):2427-2442.e4. PMC: 9271590. DOI: 10.1016/j.molcel.2022.04.032. View

14.

Zhao Y, Huang G, Wu J, Wu Q, Gao S, Yan Z . Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca Channel. Cell. 2019; 177(6):1495-1506.e12. DOI: 10.1016/j.cell.2019.04.043. View

15.

Lu Z, Klem A, Ramu Y . Ion conduction pore is conserved among potassium channels. Nature. 2001; 413(6858):809-13. DOI: 10.1038/35101535. View

16.

Bean B . The action potential in mammalian central neurons. Nat Rev Neurosci. 2007; 8(6):451-65. DOI: 10.1038/nrn2148. View

17.

Geiger J, Jonas P . Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons. Neuron. 2001; 28(3):927-39. DOI: 10.1016/s0896-6273(00)00164-1. View

18.

Hoshi T, Zagotta W, Aldrich R . Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science. 1990; 250(4980):533-8. DOI: 10.1126/science.2122519. View

19.

Hoshi T, Zagotta W, Aldrich R . Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region. Neuron. 1991; 7(4):547-56. DOI: 10.1016/0896-6273(91)90367-9. View

20.

HODGKIN A, HUXLEY A . Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol. 1952; 116(4):449-72. PMC: 1392213. DOI: 10.1113/jphysiol.1952.sp004717. View