Molecular mechanisms of coupling to voltage sensors in voltage-evoked cellular signals

Okamura, Yasushi; Okochi, Yoshifumi

doi:10.2183/pjab.95.010

Cited by 9 publications

(9 citation statements)

References 159 publications

(220 reference statements)

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“…The voltage-sensing is performed by a well-defined and highly conserved structural domain consisting of four transmembrane helices whose assembly changes conformation according to the membrane electric field. The S4 helix contains “gating charges”, positively charged amino acids that delocalise in response to the membrane electric field [ 233 ]. Structures of voltage-gated channels at different functional states suggested that the movement of gating-charge is coupled to the opening of the pore-gated domain, which adjusts its conductance according to the voltage [ 234 , 235 , 236 ].…”

Section: Cell Signalling and Sensory Motricitymentioning

confidence: 99%

Towards the Idea of Molecular Brains

Timsit

Sergeant-Perthuis

2021

IJMS

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How can single cells without nervous systems perform complex behaviours such as habituation, associative learning and decision making, which are considered the hallmark of animals with a brain? Are there molecular systems that underlie cognitive properties equivalent to those of the brain? This review follows the development of the idea of molecular brains from Darwin’s “root brain hypothesis”, through bacterial chemotaxis, to the recent discovery of neuron-like r-protein networks in the ribosome. By combining a structural biology view with a Bayesian brain approach, this review explores the evolutionary labyrinth of information processing systems across scales. Ribosomal protein networks open a window into what were probably the earliest signalling systems to emerge before the radiation of the three kingdoms. While ribosomal networks are characterised by long-lasting interactions between their protein nodes, cell signalling networks are essentially based on transient interactions. As a corollary, while signals propagated in persistent networks may be ephemeral, networks whose interactions are transient constrain signals diffusing into the cytoplasm to be durable in time, such as post-translational modifications of proteins or second messenger synthesis. The duration and nature of the signals, in turn, implies different mechanisms for the integration of multiple signals and decision making. Evolution then reinvented networks with persistent interactions with the development of nervous systems in metazoans. Ribosomal protein networks and simple nervous systems display architectural and functional analogies whose comparison could suggest scale invariance in information processing. At the molecular level, the significant complexification of eukaryotic ribosomal protein networks is associated with a burst in the acquisition of new conserved aromatic amino acids. Knowing that aromatic residues play a critical role in allosteric receptors and channels, this observation suggests a general role of π systems and their interactions with charged amino acids in multiple signal integration and information processing. We think that these findings may provide the molecular basis for designing future computers with organic processors.

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Section: Cell Signalling and Sensory Motricitymentioning

confidence: 99%

Towards the Idea of Molecular Brains

Timsit

Sergeant-Perthuis

2021

IJMS

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“…The three-dimensional protein structures of many ion channels, including some EAG subfamily channels and other members of the structurally-related CNBD family have been elucidated, initially using X-ray crystallography and NMR spectroscopy, and currently, by the spectacular improvements in single particle cryo-EM (reviewed in Vandenberg et al, 2017;Lau et al, 2018;James and Zagotta, 2018;Okamura and Okochi, 2019;Barros et al, 2019). The discovery that, despite their shared common primary organization, the EAG channels and other members of the Kv family can adopt two main architectural patterns in their transmembrane core (Figure 3), caused an essential breakthrough in our view of the structural basis of the molecular mechanism(s) involved in the voltage-triggered gating of these entities.…”

Section: Eag Channels: Prototypic Examples Of Non-domain-swapped Chanmentioning

confidence: 99%

The EAG Voltage-Dependent K+ Channel Subfamily: Similarities and Differences in Structural Organization and Gating

et al. 2020

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EAG (ether-à-go-go or KCNH) are a subfamily of the voltage-gated potassium (Kv) channels. Like for all potassium channels, opening of EAG channels drives the membrane potential toward its equilibrium value for potassium, thus setting the resting potential and repolarizing action potentials. As voltage-dependent channels, they switch between open and closed conformations (gating) when changes in membrane potential are sensed by a voltage sensing domain (VSD) which is functionally coupled to a pore domain (PD) containing the permeation pathway, the potassium selectivity filter, and the channel gate. All Kv channels are tetrameric, with four VSDs formed by the S1-S4 transmembrane segments of each subunit, surrounding a central PD with the four S5-S6 sections arranged in a square-shaped structure. Structural information, mutagenesis, and functional experiments, indicated that in "classical/Shaker-type" Kv channels voltagetriggered VSD reorganizations are transmitted to PD gating via the a-helical S4-S5 sequence that links both modules. Importantly, these Shaker-type channels share a domain-swapped VSD/PD organization, with each VSD contacting the PD of the adjacent subunit. In this case, the S4-S5 linker, acting as a rigid mechanical lever (electromechanical lever coupling), would lead to channel gate opening at the cytoplasmic S6 helices bundle. However, new functional data with EAG channels split between the VSD and PD modules indicate that, in some Kv channels, alternative VSD/PD coupling mechanisms do exist. Noticeably, recent elucidation of the architecture of some EAG channels, and other relatives, showed that their VSDs are non-domain swapped. Despite similarities in primary sequence and predicted structural organization for all EAG channels, they show marked kinetic differences whose molecular basis is not completely understood. Thus, while a common general architecture may establish the gating system used by the EAG channels and the physicochemical coupling of voltage sensing to gating, subtle changes in that common structure, and/or allosteric influences of protein domains relatively distant from the central gating machinery, can crucially influence the gating Frontiers in Pharmacology | www.frontiersin.org

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“…Based on quantum calculations, it is possible to show that at least one proton can be generated from an arginine-glutamate-tyrosine triad of amino acids in the VSD [ 7 , 12 ]. It is known that the H v 1 channel, which is very similar to the K v 1.2 VSD in its upper half (approximately) [ 13 , 14 , 15 , 16 ], does in fact transmit protons, as does bacteriorhodopsin [ 17 ]. The H v 1 results, albeit with not quite the same interpretation, have been reviewed by deCoursey [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Protons in Gating the Kv1.2 Channel: A Calculated Set of Protonation States in Response to Polarization/Depolarization of the Channel, with the Complete Proposed Proton Path from Voltage Sensing Domain to Gate

Kariev

Green

2022

Membranes

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We have in the past proposed that proton motion constitutes the gating current in the potassium channel Kv1.2 and is responsible for the gating mechanism. For this to happen, there must be a proton path between the voltage-sensing domain (VSD) and the channel gate, and here we present quantum calculations that lead to a specific pair of proton paths, defined at the molecular level, with well-defined water molecule linkages, and with hydrogen bonding between residues; there is also at least one interpath crossover, where protons can switch paths. Quantum calculations on the entire 563-atom system give the complete geometry, the energy, and atomic charges. Calculations show that three specific residues (in the pdb 3Lut numbering, H418, E327, R326), and the T1 intracellular moiety, all of which have been shown experimentally to be involved in gating, would necessarily be protonated or deprotonated in the path between the VSD and the gate. Hydroxyl reorientation of serine and threonine residues are shown to provide a means of adjusting proton directions of motion. In the deprotonated state for K312, a low energy state, our calculations come close to reproducing the X-ray structure. The demonstration of the existence of a double proton path between VSD and gate supports the proposed proton gating mechanism; when combined with our earlier demonstration of proton generation in the VSD, and comparison with other systems that are known to move protons, we are close to achieving the definition of a complete gating mechanism in molecular detail. The coupling of the paths to the VSD, and to the PVPV section that essentially forms the gate, can be easily seen from the results of the calculation. The gate itself remains for further computations.

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Molecular mechanisms of coupling to voltage sensors in voltage-evoked cellular signals

Cited by 9 publications

References 159 publications

Towards the Idea of Molecular Brains

Towards the Idea of Molecular Brains

The EAG Voltage-Dependent K+ Channel Subfamily: Similarities and Differences in Structural Organization and Gating

Protons in Gating the Kv1.2 Channel: A Calculated Set of Protonation States in Response to Polarization/Depolarization of the Channel, with the Complete Proposed Proton Path from Voltage Sensing Domain to Gate

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