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Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel.

Zheng Y, Liu H, Chen Y, Dong S, Wang F, Wang S, Li GL, Shu Y, Xu F
Neuron 110 237-247.e4 (2022)
Related entries: 7vnp, 7vnr

Cited: 24 times
EuropePMC logo PMID: 34767770

Abstract

The KCNQ family (KCNQ1-KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on the signaling lipid molecule phosphatidylinositol 4,5-bisphosphate (PIP2). However, the molecular mechanism of PIP2 in modulating the opening of the four neuronal KCNQ channels (KCNQ2-KCNQ5), which are essential for regulating neuronal excitability, remains largely elusive. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 determined in complex with the activator ML213 in the absence or presence of PIP2. Two PIP2 molecules are identified in the open-state structure of KCNQ4, which act as a bridge to couple the voltage-sensing domain (VSD) and pore domain (PD) of KCNQ4 leading to the channel opening. Our findings reveal the binding sites and activation mechanisms of ML213 and PIP2 for neuronal KCNQ channels, providing a framework for therapeutic intervention targeting on these important channels.

Articles - 7vnq mentioned but not cited (1)

  1. Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277. Willegems K, Eldstrom J, Kyriakis E, Ataei F, Sahakyan H, Dou Y, Russo S, Van Petegem F, Fedida D. Nat Commun 13 3760 (2022)


Reviews citing this publication (3)

  1. The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants. Homma K. Biomedicines 10 2254 (2022)
  2. Spotlight on the Binding Affinity of Ion Channels for Phosphoinositides: From the Study of Sperm Flagellum. Kawai T, Okamura Y. Front Physiol 13 834180 (2022)
  3. Start Me Up: How Can Surrounding Gangliosides Affect Sodium-Potassium ATPase Activity and Steer towards Pathological Ion Imbalance in Neurons? Puljko B, Stojanović M, Ilic K, Kalanj-Bognar S, Mlinac-Jerkovic K. Biomedicines 10 1518 (2022)

Articles citing this publication (20)

  1. Precise detection of CRISPR-Cas9 editing in hair cells in the treatment of autosomal dominant hearing loss. Cui C, Wang D, Huang B, Wang F, Chen Y, Lv J, Zhang L, Han L, Liu D, Chen ZY, Li GL, Li H, Shu Y. Mol Ther Nucleic Acids 29 400-412 (2022)
  2. Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers. Ma D, Zhong L, Yan Z, Yao J, Zhang Y, Ye F, Huang Y, Lai D, Yang W, Hou P, Guo J. Proc Natl Acad Sci U S A 119 e2207067119 (2022)
  3. Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1. Schmidpeter PAM, Petroff JT, Khajoueinejad L, Wague A, Frankfater C, Cheng WWL, Nimigean CM, Riegelhaupt PM. Nat Commun 14 1077 (2023)
  4. Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability. Wei AD, Wakenight P, Zwingman TA, Bard AM, Sahai N, Willemsen MH, Schelhaas HJ, Stegmann APA, Verhoeven JS, de Man SA, Wessels MW, Kleefstra T, Shinde DN, Helbig KL, Basinger A, Wagner VF, Rodriguez-Buritica D, Bryant E, Millichap JJ, Millen KJ, Dobyns WB, Ramirez JM, Kalume FK. J Neurophysiol 128 40-61 (2022)
  5. The membrane electric field regulates the PIP2-binding site to gate the KCNQ1 channel. Mandala VS, MacKinnon R. Proc Natl Acad Sci U S A 120 e2301985120 (2023)
  6. Biophysical physiology of phosphoinositide rapid dynamics and regulation in living cells. Jensen JB, Falkenburger BH, Dickson EJ, de la Cruz L, Dai G, Myeong J, Jung SR, Kruse M, Vivas O, Suh BC, Hille B. J Gen Physiol 154 e202113074 (2022)
  7. Molecular architecture of the Gαi-bound TRPC5 ion channel. Won J, Kim J, Jeong H, Kim J, Feng S, Jeong B, Kwak M, Ko J, Im W, So I, Lee HH. Nat Commun 14 2550 (2023)
  8. Ancient medicinal plant rosemary contains a highly efficacious and isoform-selective KCNQ potassium channel opener. Manville RW, Hogenkamp D, Abbott GW. Commun Biol 6 644 (2023)
  9. Intracellular zinc protects Kv7 K+ channels from Ca2+/calmodulin-mediated inhibition. Yang X, Chen S, Zhang S, Shi S, Zong R, Gao Y, Guan B, Gamper N, Gao H. J Biol Chem 299 102819 (2023)
  10. Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies. Krüger J, Schubert J, Kegele J, Labalme A, Mao M, Heighway J, Seebohm G, Yan P, Koko M, Aslan-Kara K, Caglayan H, Steinhoff BJ, Weber YG, Keo-Kosal P, Berkovic SF, Hildebrand MS, Petrou S, Krause R, May P, Lesca G, Maljevic S, Lerche H. EBioMedicine 84 104244 (2022)
  11. A small-molecule activation mechanism that directly opens the KCNQ2 channel. Zhang S, Ma D, Wang K, Li Y, Yang Z, Li X, Li J, He J, Mei L, Ye Y, Chen Z, Shen J, Hou P, Guo J, Zhang Q, Yang H. Nat Chem Biol (2024)
  12. Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine. Yang ND, Kanyo R, Zhao L, Li J, Kang PW, Dou AK, White KM, Shi J, Nerbonne JM, Kurata HT, Cui J. Sci Adv 8 eabo3625 (2022)
  13. Functional characterization and in vitro pharmacological rescue of KCNQ2 pore mutations associated with epileptic encephalopathy. Yang GM, Tian FY, Shen YW, Yang CY, Yuan H, Li P, Gao ZB. Acta Pharmacol Sin 44 1589-1599 (2023)
  14. Ligand activation mechanisms of human KCNQ2 channel. Ma D, Zheng Y, Li X, Zhou X, Yang Z, Zhang Y, Wang L, Zhang W, Fang J, Zhao G, Hou P, Nan F, Yang W, Su N, Gao Z, Guo J. Nat Commun 14 6632 (2023)
  15. Overlooked KCNQ4 variants augment the risk of hearing loss. Oh KS, Roh JW, Joo SY, Ryu K, Kim JA, Kim SJ, Jang SH, Koh YI, Kim DH, Kim HY, Choi M, Jung J, Namkung W, Nam JH, Choi JY, Gee HY. Exp Mol Med 55 844-859 (2023)
  16. Redox regulation of KV7 channels through EF3 hand of calmodulin. Nuñez E, Jones F, Muguruza-Montero A, Urrutia J, Aguado A, Malo C, Bernardo-Seisdedos G, Domene C, Millet O, Gamper N, Villarroel A. Elife 12 e81961 (2023)
  17. Site and Mechanism of ML252 Inhibition of Kv7 Voltage-Gated Potassium Channels. Kanyo R, Lamothe SM, Urrutia A, Goodchild SJ, Allison WT, Dean R, Kurata HT. Function (Oxf) 4 zqad021 (2023)
  18. Bidirectional Allosteric Coupling between PIP2 Binding and the Pore of the Oncochannel TRPV6. Humer C, Radiskovic T, Horváti K, Lindinger S, Groschner K, Romanin C, Höglinger C. Int J Mol Sci 25 618 (2024)
  19. Dehydroepiandrosterone Sulfate (DHEAS) Is an Endogenous Kv7 Channel Modulator That Reduces Kv7/M-Current Suppression and Inflammatory Pain. Alhassen L, Alhassen W, Wong C, Sun Y, Xia Z, Civelli O, Hoshi N. J Neurosci 43 7073-7083 (2023)
  20. Structural insights into human organic cation transporter 1 transport and inhibition. Zhang S, Zhu A, Kong F, Chen J, Lan B, He G, Gao K, Cheng L, Sun X, Yan C, Chen L, Liu X. Cell Discov 10 30 (2024)


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