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Intracellular electric field and pH optimize protein localization and movement.

ABSTRACT: Mammalian cell function requires timely and accurate transmission of information from the cell membrane (CM) to the nucleus (N). These pathways have been intensively investigated and many critical components and interactions have been identified. However, the physical forces that control movement of these proteins have received scant attention. Thus, transduction pathways are typically presented schematically with little regard to spatial constraints that might affect the underlying dynamics necessary for protein-protein interactions and molecular movement from the CM to the N. We propose messenger protein localization and movements are highly regulated and governed by Coulomb interactions between: 1. A recently discovered, radially directed E-field from the NM into the CM and 2. Net protein charge determined by its isoelectric point, phosphorylation state, and the cytosolic pH. These interactions, which are widely applied in elecrophoresis, provide a previously unknown mechanism for localization of messenger proteins within the cytoplasm as well as rapid shuttling between the CM and N. Here we show these dynamics optimize the speed, accuracy and efficiency of transduction pathways even allowing measurement of the location and timing of ligand binding at the CM--previously unknown components of intracellular information flow that are, nevertheless, likely necessary for detecting spatial gradients and temporal fluctuations in ligand concentrations within the environment. The model has been applied to the RAF-MEK-ERK pathway and scaffolding protein KSR1 using computer simulations and in-vitro experiments. The computer simulations predicted distinct distributions of phosphorylated and unphosphorylated components of this transduction pathway which were experimentally confirmed in normal breast epithelial cells (HMEC).

SUBMITTER: Cunningham J

PROVIDER: S-EPMC3356409 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Intracellular electric field and pH optimize protein localization and movement.

Cunningham Jessica J Estrella Veronica V Lloyd Mark M Gillies Robert R Frieden B Roy BR Gatenby Robert R

PloS one 20120518 5

Mammalian cell function requires timely and accurate transmission of information from the cell membrane (CM) to the nucleus (N). These pathways have been intensively investigated and many critical components and interactions have been identified. However, the physical forces that control movement of these proteins have received scant attention. Thus, transduction pathways are typically presented schematically with little regard to spatial constraints that might affect the underlying dynamics nec ...[more]

PMID: 22623963

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Project description:ObjectiveCerebellar transcranial direct current stimulation (ctDCS) is challenging due to the complexity of the cerebellar structure which is reflected by the well-known variability in ctDCS effects. Therefore, our objective is to present a freely available computational modeling pipeline for cerebellar lobules' optimal stimulation (CLOS).MethodsCLOS can optimize lobule-specific electric field distribution following finite element analysis (FEA) using freely available computational modeling pipelines. We modeled published ctDCS montages with 5 cm × 5 cm anode placed 3 cm lateral to inion, and the same sized cathode was placed on the: (1) contralateral supra-orbital area (called Manto montage), and (2) buccinators muscle (called Celnik montage). Also, a published (3) 4×1 HD-ctDCS electrode montage was modeled. We also investigated the effects of the subject-specific head model versus Colin 27 average head model on lobule-specific electric field distribution. Three-way analysis of variance (ANOVA) was used to determine the effects of lobules, montage, and head model on the electric field distribution. The differences in lobule-specific electric field distribution across different freely available computational pipelines were also evaluated using subject-specific head model. We also presented an application of our computational pipeline to optimize a ctDCS electrode montage to deliver peak electric field at the cerebellar lobules VII-IX related to ankle function.ResultsEta-squared effect size after three-way ANOVA for electric field strength was 0.05 for lobule, 0.00 for montage, 0.04 for the head model, 0.01 for lobule?montage interaction, 0.01 for lobule? head model interaction, and 0.00 for montage?head model interaction. The electric field strength of both the Celnik and the Manto montages affected the lobules Crus I/II, VIIb, VIII, and IX of the targeted cerebellar hemisphere where Manto montage had a spillover to the contralateral cerebellar hemisphere. The 4×1 HD-ctDCS montage primarily affected the lobules Crus I/II of the targeted cerebellar hemisphere. All three published ctDCS montages were found to be not optimal for ankle function (lobules VII-IX), so we presented a novel HD-ctDCS electrode montage.DiscussionOur freely available CLOS pipeline can be leveraged to optimize electromagnetic stimulation to target cerebellar lobules related to different cognitive and motor functions.

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Intracellular electric field and pH optimize protein localization and movement.

Publications

Intracellular electric field and pH optimize protein localization and movement.

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