scholarly journals Two-stage electro-mechanical coupling of a KV channel in voltage-dependent activation

2019 ◽  
Author(s):  
Panpan Hou ◽  
Po Wei Kang ◽  
Audrey Deyawe Kongmeneck ◽  
Nien-Du Yang ◽  
Yongfeng Liu ◽  
...  
Keyword(s):  
Coupling Mechanism ◽  
Two Stage ◽  
Mechanical Coupling ◽  
Kv Channel ◽  
Gating Mechanism ◽  
C Terminus ◽  
Activated State ◽  
Voltage Dependent ◽  
Open States ◽  
Voltage Sensing Domain

AbstractIn voltage-gated potassium (KV) channels, the voltage-sensing domain (VSD) undergoes sequential activation from the resting state to the intermediate state and activated state to trigger pore opening via electro-mechanical (E-M) coupling. However, the spatial and temporal details underlying E-M coupling remain elusive. Here, we leverage KV7.1’s unique two open states associated with the VSD adopting the intermediate and activated conformations to report a two-stage E-M coupling mechanism in voltage-dependent gating of KV7.1 as triggered by VSD activations to the intermediate and then activated state. When the S4 segment transitions to the intermediate state, the hand-like C-terminus of the VSD-pore linker (S4-S5L) interacts with the pore in the same subunit. When S4 then proceeds on to the fully-activated state, the elbow-like hinge between S4 and S4-S5L engages with the pore to activate conductance. This two-stage “hand-and-elbow” gating mechanism elucidates distinct tissue-specific modulations, pharmacology, and disease pathogenesis of KV7.1, and likely applies to numerous KV channels.

scholarly journals Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening

2020 ◽  
Vol 6 (50) ◽  
pp. eabd6798
Author(s):  
Po Wei Kang ◽  
Annie M. Westerlund ◽  
Jingyi Shi ◽  
Kelli McFarland White ◽  
Alex K. Dou ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Conformational Changes ◽  
State Dependent ◽  
Gating Mechanism ◽  
Channel Opening ◽  
Activated State ◽  
Voltage Dependent ◽  
Functional Consequences ◽  
Open States ◽  
Voltage Sensing Domain

Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP2) are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the cardiac IKs current. Although cryo–electron microscopy structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully activated state allows PIP2 to compete with CaM for binding to VSD. This leads to conformational changes that alter VSD-pore coupling to stabilize open states. We identify a motif in the KCNQ1 cytosolic domain, which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its physiological function.

scholarly journals Two-stage electro–mechanical coupling of a KV channel in voltage-dependent activation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Panpan Hou ◽  
Po Wei Kang ◽  
Audrey Deyawe Kongmeneck ◽  
Nien-Du Yang ◽  
Yongfeng Liu ◽  
...  
Keyword(s):  
Two Stage ◽  
Mechanical Coupling ◽  
Kv Channel ◽  
Voltage Dependent

scholarly journals Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening

2020 ◽  
Author(s):  
Po Wei Kang ◽  
Annie M. Westerlund ◽  
Jingyi Shi ◽  
Kelli McFarland White ◽  
Alex K. Dou ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Conformational Change ◽  
State Dependent ◽  
Gating Mechanism ◽  
Channel Opening ◽  
Activated State ◽  
Voltage Dependent ◽  
Functional Consequences ◽  
Pore Opening ◽  
Voltage Sensing Domain

AbstractCalmodulin (CaM) and PIP2 are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the IKs current important for repolarization of cardiac action potentials. Although cryo-EM structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully-activated state allows PIP2 to compete with CaM for binding to VSD, leading to the conformational change that alters the VSD-pore coupling. We identify a motif in the KCNQ1 cytosolic domain which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its function in the heart.

scholarly journals ML277 specifically enhances pore opening of KCNQ1 with VSD at the activated state by modulating VSD-pore coupling

2019 ◽  
Author(s):  
Panpan Hou ◽  
Jingyi Shi ◽  
Kelli McFarland White ◽  
Yuan Gao ◽  
Jianmin Cui
Keyword(s):  
Voltage Dependence ◽  
Heart Rhythm ◽  
Inactivation Kinetics ◽  
Loss Of Function ◽  
Auxiliary Subunit ◽  
Gating Mechanism ◽  
Activated State ◽  
New Strategy ◽  
Pore Opening ◽  
Voltage Sensing Domain

AbstractIn response to membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states that correspond to the stepwise activation of the voltage sensing domain (VSD) to the intermediate (I) and activated (A) states. In the heart, KCNQ1 associates with the auxiliary subunit KCNE1 to form the IKs channel that regulates heart rhythm. More than 300 of loss-of-function KCNQ1 mutations cause long QT syndrome (LQTS). KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Thus, enhancing AO state presents a potential therapy for anti-LQTS. Here, we systematically tested modulations of KCNQ1 channels by a KCNQ1 activator, ML277. It enhances the current amplitude, slows down activation, deactivation and inactivation kinetics, shifts the voltage dependence of activation to more positive voltages, decreases the Rb+/K+ permeability ratio, and selectively increases currents of mutant KCNQ1 channels that open only to the AO state. All these observations are consistent with the mechanism that ML277 specifically potentiates the AO state. On the other hand, ML277 does not affect the VSD activation, suggesting that it potentiates the AO state by enhancing the electromechanical (E-M) coupling when the VSD moves to the activated state. Our results suggest that ML277 provides a unique tool to investigate the gating mechanism of KCNQ1 and IKs channels. The specificity of ML277 to increase the AO state of native IKs currents also suggests a new strategy for anti-LQTS therapy.

scholarly journals Two-stage “Hand-and-Elbow” Gating Mechanism of a KV Channel

2020 ◽  
Vol 118 (3) ◽  
pp. 113a
Author(s):  
Panpan Hou ◽  
Po Wei Kang ◽  
Audrey Deyawe Kongmeneck ◽  
Nien-Du Yang ◽  
Yongfeng Liu ◽  
...  
Keyword(s):  
Two Stage ◽  
Kv Channel ◽  
Gating Mechanism

scholarly journals The isolated voltage sensing domain of the Shaker potassium channel forms a voltage-gated cation channel

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Juan Zhao ◽  
Rikard Blunck
Keyword(s):  
Transmembrane Helix ◽  
Voltage Sensing ◽  
Shaker Potassium Channel ◽  
Voltage Gated ◽  
Kv Channel ◽  
C Terminus ◽  
Ion Conducting ◽  
Voltage Gated Ion Channels ◽  
Voltage Sensing Domain ◽  
Pore Domain

Domains in macromolecular complexes are often considered structurally and functionally conserved while energetically coupled to each other. In the modular voltage-gated ion channels the central ion-conducting pore is surrounded by four voltage sensing domains (VSDs). Here, the energetic coupling is mediated by interactions between the S4-S5 linker, covalently linking the domains, and the proximal C-terminus. In order to characterize the intrinsic gating of the voltage sensing domain in the absence of the pore domain, the Shaker Kv channel was truncated after the fourth transmembrane helix S4 (Shaker-iVSD). Shaker-iVSD showed significantly altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons. Ion conduction in Shaker-iVSD developed despite identical primary sequence, indicating an allosteric influence of the pore domain. Shaker-iVSD also displays pronounced 'relaxation'. Closing of the pore correlates with entry into relaxation suggesting that the two processes are energetically related.

scholarly journals Structural basis of gating modulation of Kv4 channel complexes

Nature ◽  
2021 ◽  
Author(s):  
Yoshiaki Kise ◽  
Go Kasuya ◽  
Hiroyuki H. Okamoto ◽  
Daichi Yamanouchi ◽  
Kan Kobayashi ◽  
...  
Keyword(s):  
Structural Basis ◽  
Macromolecular Complex ◽  
Auxiliary Subunits ◽  
Voltage Gated ◽  
Kv Channels ◽  
C Terminus ◽  
Voltage Dependent ◽  
Gated Channel ◽  
Related Proteins ◽  
Voltage Sensing Domain

AbstractModulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart1,2. Native Kv4 tetrameric channels form macromolecular ternary complexes with two auxiliary β-subunits—intracellular Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-related proteins (DPPs)—to evoke rapidly activating and inactivating A-type currents, which prevent the backpropagation of action potentials1–5. However, the modulatory mechanisms of Kv4 channel complexes remain largely unknown. Here we report cryo-electron microscopy structures of the Kv4.2–DPP6S–KChIP1 dodecamer complex, the Kv4.2–KChIP1 and Kv4.2–DPP6S octamer complexes, and Kv4.2 alone. The structure of the Kv4.2–KChIP1 complex reveals that the intracellular N terminus of Kv4.2 interacts with its C terminus that extends from the S6 gating helix of the neighbouring Kv4.2 subunit. KChIP1 captures both the N and the C terminus of Kv4.2. In consequence, KChIP1 would prevent N-type inactivation and stabilize the S6 conformation to modulate gating of the S6 helices within the tetramer. By contrast, unlike the reported auxiliary subunits of voltage-gated channel complexes, DPP6S interacts with the S1 and S2 helices of the Kv4.2 voltage-sensing domain, which suggests that DPP6S stabilizes the conformation of the S1–S2 helices. DPP6S may therefore accelerate the voltage-dependent movement of the S4 helices. KChIP1 and DPP6S do not directly interact with each other in the Kv4.2–KChIP1–DPP6S ternary complex. Thus, our data suggest that two distinct modes of modulation contribute in an additive manner to evoke A-type currents from the native Kv4 macromolecular complex.

scholarly journals Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain

2014 ◽  
Vol 21 (3) ◽  
pp. 244-252 ◽  
Author(s):  
Qufei Li ◽  
Sherry Wanderling ◽  
Marcin Paduch ◽  
David Medovoy ◽  
Abhishek Singharoy ◽  
...  
Keyword(s):  
Voltage Sensing ◽  
Structural Mechanism ◽  
Voltage Dependent ◽  
Voltage Sensing Domain

scholarly journals The C Terminus of Cardiac Troponin I Stabilizes the Ca 2+ -Activated State of Tropomyosin on Actin Filaments

2010 ◽  
Vol 106 (4) ◽  
pp. 705-711 ◽  
Author(s):  
Agnieszka Galińska ◽  
Victoria Hatch ◽  
Roger Craig ◽  
Anne M. Murphy ◽  
Jennifer E. Van Eyk ◽  
...  
Keyword(s):  
Actin Filaments ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Cardiac Troponin I ◽  
C Terminus ◽  
Activated State

scholarly journals Hydrophobic gasket mutation produces gating pore currents in closed human voltage-gated proton channels

2019 ◽  
Vol 116 (38) ◽  
pp. 18951-18961 ◽  
Author(s):  
Richard Banh ◽  
Vladimir V. Cherny ◽  
Deri Morgan ◽  
Boris Musset ◽  
Sarah Thomas ◽  
...  
Keyword(s):  
Proton Channel ◽  
Voltage Gated ◽  
Closed State ◽  
Channel Opening ◽  
Proton Current ◽  
Voltage Dependent ◽  
Current Flows ◽  
Voltage Gated Ion Channels ◽  
Dynamics Simulations ◽  
Voltage Sensing Domain

The hydrophobic gasket (HG), a ring of hydrophobic amino acids in the voltage-sensing domain of most voltage-gated ion channels, forms a constriction between internal and external aqueous vestibules. Cationic Arg or Lys side chains lining the S4 helix move through this “gating pore” when the channel opens. S4 movement may occur during gating of the human voltage-gated proton channel, hHV1, but proton current flows through the same pore in open channels. Here, we replaced putative HG residues with less hydrophobic residues or acidic Asp. Substitution of individuals, pairs, or all 3 HG positions did not impair proton selectivity. Evidently, the HG does not act as a secondary selectivity filter. However, 2 unexpected functions of the HG in HV1 were discovered. Mutating HG residues independently accelerated channel opening and compromised the closed state. Mutants exhibited open–closed gating, but strikingly, at negative voltages where “normal” gating produces a nonconducting closed state, the channel leaked protons. Closed-channel proton current was smaller than open-channel current and was inhibited by 10 μM Zn2+. Extreme hyperpolarization produced a deeper closed state through a weakly voltage-dependent transition. We functionally identify the HG as Val109, Phe150, Val177, and Val178, which play a critical and exclusive role in preventing H+ influx through closed channels. Molecular dynamics simulations revealed enhanced mobility of Arg208 in mutants exhibiting H+ leak. Mutation of HG residues produces gating pore currents reminiscent of several channelopathies.

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