Ion channels as lipid sensors: from structures to mechanisms

Thompson, Mackenzie J.; Baenziger, John E.

doi:10.1038/s41589-020-00693-3

Cited by 53 publications

(40 citation statements)

References 103 publications

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“…However, the large values of the slope factor of 60-100mV, which did not differ much between the WT and E7K mutant or change before and after DrVSP-mediated PIP 2 depletion (see the Figure 4 legend), indicate that the effective number of gating charges involved in the voltage-dependent activation of the TRPM4 channel would be far less than one, which is much smaller than those of purely voltage-dependent channels [ 27 ]. Therefore, the observed shift of the voltage-dependent activation curve for WT-TRPM4 channels upon PIP 2 depletion ( Figure 4 ) would most likely reflect the voltage-independent conformational energy decrease resulting from the release of PIP 2 -mediated ‘steric interactions’ within the channel complex which are essential for its activity [ 28 ]. These interactions would be strongly tightened in the E7K mutant, and this may be the reason why vigorous, but not complete, PIP 2 depletion by DrVSP activation resulted in only a marginal decrease of E7K channel activity.…”

Section: Discussionmentioning

confidence: 99%

An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction

Kurahara

et al. 2021

Cells

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A Ca2+-activated monovalent cation-selective TRPM4 channel is abundantly expressed in the heart. Recently, a single gain-of-function mutation identified in the distal N-terminus of the human TRPM4 channel (Glu5 to Lys5; E7K) was found to be arrhythmogenic because of enhanced cell membrane expression. In this study, we conducted detailed analyses of this mutant channel from more functional aspects, in comparison with its wild type (WT). In an expression system, intracellular application of a short soluble PIP2 (diC8PIP2) restored the single-channel activities of both WT and E7K, which had quickly faded after membrane excision. The potency (Kd) of diC8PIP2 for this recovery was stronger in E7K than its WT (1.44 vs. 2.40 μM). FRET-based PIP2 measurements combined with the Danio rerio voltage-sensing phosphatase (DrVSP) and patch clamping revealed that lowering the endogenous PIP2 level by DrVSP activation reduced the TRPM4 channel activity. This effect was less prominent in E7K than its WT (apparent Kd values estimated from DrVSP-mediated PIP2 depletion: 0.97 and 1.06 μM, respectively), being associated with the differential PIP2-mediated modulation of voltage dependence. Moreover, intracellular perfusion of short N-terminal polypeptides containing either the ‘WT’ or ‘E7K’ sequences respectively attenuated the TRPM4 channel activation at whole-cell and single-channel levels, but in both configurations, the E7K polypeptide exerted greater inhibitory effects. These results collectively suggest that N-terminal interaction with endogenous PIP2 is essential for the TRPM4 channel to function, the extent of which may be abnormally strengthened by the E7K mutation through modulating voltage-dependent activation. The altered PIP2 interaction may account for the arrhythmogenic potential of this mutation.

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Section: Discussionmentioning

confidence: 99%

An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction

Kurahara

et al. 2021

Cells

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“…There are also channels whose opening is controlled by ligand binding, of which there are several families such as pentameric ligand-gated channel, glutamate-gated channel, K ATP channels [ 284 ]. In addition, some channels whose opening is triggered by physical stimuli can also be controlled by specific membrane lipids [ 285 ]. Although these families have different architecture and evolved from different structures, they share a modular organisation of intra- and extra-membrane domains that allows the conversion of ligand binding into an electrical signal by controlling the opening of transmembrane ion channels.…”

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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“…The charge‐transfer‐related proteins are known to respond to numerous cues within the microenvironment such as chemical agents, temperature, [ 80 ] electrical potential, [ 81 ] osmolarity, and mechanical stimuli. [ 37,82 ] Implants that modulate the above factors are expected to control the activation of the charge‐transfer‐related proteins.…”

Section: Strategies To Monitor and Regulate The Transmembrane Charge Transfermentioning

confidence: 99%

Biomedical Implants with Charge‐Transfer Monitoring and Regulating Abilities

et al. 2021

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Transmembrane charge (ion/electron) transfer is essential for maintaining cellular homeostasis and is involved in many biological processes, from protein synthesis to embryonic development in organisms. Designing implant devices that can detect or regulate cellular transmembrane charge transfer is expected to sense and modulate the behaviors of host cells and tissues. Thus, charge transfer can be regarded as a bridge connecting living systems and human‐made implantable devices. This review describes the mode and mechanism of charge transfer between organisms and nonliving materials, and summarizes the strategies to endow implants with charge‐transfer regulating or monitoring abilities. Furthermore, three major charge‐transfer controlling systems, including wired, self‐activated, and stimuli‐responsive biomedical implants, as well as the design principles and pivotal materials are systematically elaborated. The clinical challenges and the prospects for future development of these implant devices are also discussed.

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Ion channels as lipid sensors: from structures to mechanisms

Cited by 53 publications

References 103 publications

An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction

An Arrhythmic Mutation E7K Facilitates TRPM4 Channel Activation via Enhanced PIP2 Interaction

Towards the Idea of Molecular Brains

Biomedical Implants with Charge‐Transfer Monitoring and Regulating Abilities

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