Clusters of cooperative ion channels enable a membrane-potential-based mechanism for short-term memory

Pfeiffer, Paul; Egorov, Alexei V.; Lorenz, Franziska; Schleimer, Jan-Hendrik; Draguhn, Andreas; Schreiber, Susanne

doi:10.7554/elife.49974

Cited by 25 publications

(23 citation statements)

References 58 publications

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“…Any abnormal transmission results in disordered trans-synaptic signaling and membrane potential. The membrane potential in the CNS may contribute to memory formation [ 33 ]. Then the protein–protein interaction (PPI) analysis was conducted, A protein cluster including PENK, CNR1, CALB1, TAC1, SST, GNG, CCK, BDNF, GAD1 and was identified and was transferred to the GO and KEGG analyses ( Figure 3(a-e) ).…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease

Liu

Jiang

et al. 2021

Bioengineered

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Alzheimer’s Disease (AD) is a neurodegenerative disease featured by cognitive impairment. This bioinformatic analysis was used to identify hub genes related to cognitive dysfunction in AD. The gene expression profile GSE48350 in the hippocampus of AD patients aged >70 years was obtained from the Gene Expression Omnibus (GEO) database. A total of 96 differentially expressed genes (DEGs) were identified, and subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses; a protein–protein interaction (PPI) network was constructed. The DEGs were enriched in synapse-related changes. A protein cluster was teased out of PPI. Furthermore, the cognition ranked the first among all the terms of biological process (BP). Next, 4 of 10 hub genes enriched in cognition were identified. The function of these genes was validated using APP/PS1 mice. Cognitive performance was validated by Morris Water Maze (MWM), and gene expression by RT-qPCR, Cholecystokinin ( CCK ), Tachykinin precursor 1 ( TAC1 ), Calbindin 1 ( CALB1 ) were downregulated in the hippocampus. These genes can provide new directions in the research of the molecular mechanism of AD.

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Section: Discussionmentioning

confidence: 99%

Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease

Liu

Jiang

et al. 2021

Bioengineered

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“…This coupling is increased by ß-adrenergic stimulation [ 49 ]. In the brain, functional coupling has been shown for BK and Ca v 1.3 channels, and cooperative gating has been suggested to play a role in short-term memory [ 50 , 51 ]. Lastly, voltage-gated proton channels that are expressed in many organisms and tissues are also shown to gate cooperatively [ 52 – 54 ].…”

Section: Discussionmentioning

confidence: 99%

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Na_v1.5

et al. 2020

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The cardiac voltage-gated sodium channel Na v 1.5 conducts the rapid inward sodium current crucial for cardiomyocyte excitability. Loss-of-function mutations in its gene SCN5A are linked to cardiac arrhythmias such as Brugada Syndrome (BrS). Several BrS-associated mutations in the Na v 1.5 N-terminal domain (NTD) exert a dominant-negative effect (DNE) on wild-type channel function, for which mechanisms remain poorly understood. We aim to contribute to the understanding of BrS pathophysiology by characterizing three mutations in the Na v 1.5 NTD: Y87C-here newly identified-, R104W, and R121W. In addition, we hypothesize that the calcium sensor protein calmodulin is a new NTD binding partner. Recordings of whole-cell sodium currents in TsA-201 cells expressing WT and variant Na v 1.5 showed that Y87C and R104W but not R121W exert a DNE on WT channels. Biotinylation assays revealed reduction in fully glycosylated Na v 1.5 at the cell surface and in whole-cell lysates. Localization of Na v 1.5 WT channel with the ER did not change in the presence of variants, as shown by transfected and stained rat neonatal cardiomyocytes. We demonstrated that calmodulin binds the Na v 1.5 NTD using in silico modeling, SPOTS, pull-down, and proximity ligation assays. Calmodulin binding to the R121W variant and to a Na v 1.5 construct missing residues 80-105, a predicted calmodulin-binding site, is impaired. In conclusion, we describe the new natural BrS Na v 1.5 variant Y87C and present first evidence that calmodulin binds to the Na v 1.5 NTD, which seems to be a determinant for the DNE.

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“…Finally, while our approach could in principle be extended to large clusters of Na + channels, it may lead to very large matrices that computationally may become less tractable. For this purpose, phenomenological approaches to model channel cooperativity may be an advantage (Naundorf et al, 2006;Pfeiffer et al, 2020).…”

Section: Limitationsmentioning

confidence: 99%

Modeling the Interactions Between Sodium Channels Provides Insight Into the Negative Dominance of Certain Channel Mutations

2020

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Background: Na v 1.5 cardiac Na + channel mutations can cause arrhythmogenic syndromes. Some of these mutations exert a dominant negative effect on wild-type channels. Recent studies showed that Na + channels can dimerize, allowing coupled gating. This leads to the hypothesis that allosteric interactions between Na + channels modulate their function and that these interactions may contribute to the negative dominance of certain mutations. Methods: To investigate how allosteric interactions affect microscopic and macroscopic channel function, we developed a modeling paradigm in which Markovian models of two channels are combined. Allosteric interactions are incorporated by modifying the free energies of the composite states and/or barriers between states. Results: Simulations using two generic 2-state models (C-O, closed-open) revealed that increasing the free energy of the composite states CO/OC leads to coupled gating. Simulations using two 3-state models (closed-open-inactivated) revealed that coupled closings must also involve interactions between further composite states. Using two 6-state cardiac Na + channel models, we replicated previous experimental results mainly by increasing the energies of the CO/OC states and lowering the energy barriers between the CO/OC and the CO/OO states. The channel model was then modified to simulate a negative dominant mutation (Na v 1.5 p.L325R). Simulations of homodimers and heterodimers in the presence and absence of interactions showed that the interactions with the variant channel impair the opening of the wild-type channel and thus contribute to negative dominance.

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Clusters of cooperative ion channels enable a membrane-potential-based mechanism for short-term memory

Cited by 25 publications

References 58 publications

Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease

Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Na_v1.5

Modeling the Interactions Between Sodium Channels Provides Insight Into the Negative Dominance of Certain Channel Mutations

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Clusters of cooperative ion channels enable a membrane-potential-based mechanism for short-term memory

Cited by 25 publications

References 58 publications

Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease

Identification of hub genes associated with cognition in the hippocampus of Alzheimer’s Disease

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Nav1.5

Modeling the Interactions Between Sodium Channels Provides Insight Into the Negative Dominance of Certain Channel Mutations

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Calmodulin binds to the N-terminal domain of the cardiac sodium channel Na_v1.5