Modulation of metabolic communication through gap junction channels by transjunctional voltage; synergistic and antagonistic effects of gating and ionophoresis

Palacios-Prado, Nicolás; Bukauskas, Feliksas F.

doi:10.1016/j.bbamem.2011.09.001

Cited by 41 publications

(45 citation statements)

References 78 publications

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“…Cell-to-cell transfer of atomic ions and metabolites depends also on ionophoresis by V j , which can accelerate or decelerate the motion of charged molecules in the GJ channel pore (Palacios-Prado and Bukauskas 2012). Thus, metabolic cell–cell communication depends on the permeability of GJs, their number and V j .…”

Section: Discussionmentioning

confidence: 99%

Neurons and β-Cells of the Pancreas Express Connexin36, Forming Gap Junction Channels that Exhibit Strong Cationic Selectivity

Bukauskas

2012

J Membrane Biol

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We examined the permeability of connexin36 (Cx36) homotypic gap junction (GJ) channels, expressed in neurons and β-cells of the pancreas, to dyes differing in molecular mass and net charge. Experiments were performed in HeLa cells stably expressing Cx36 tagged with EGFP by combining a dual whole-cell voltage clamp and fluorescence imaging. To assess the permeability of the single GJ channel (Pγ), we used a dual-mode excitation of fluorescent dyes that allowed us to measure cell-to-cell dye transfer at levels not resolvable using whole-field excitation solely. We demonstrate that Pγ of Cx36 for cationic dyes (EAM-1+ and EAM-2+) is ∼10-fold higher than that for an anionic dye of the same net charge and similar molecular mass, Alexa fluor-350 (AFl-350−). In addition, Pγ for Lucifer yellow (LY2−) is approximately fourfold smaller than that for AFl-350−, which suggests that the higher negativity of LY2− significantly reduces permeability. The Pγ of Cx36 for AFl-350 is approximately 358, 138, 23 and four times smaller than the Pγs of Cx43, Cx40, Cx45, and Cx57, respectively. In contrast, it is 6.5-fold higher than the Pγ of mCx30.2, which exhibits a smaller single-channel conductance. Thus, Cx36 GJs are highly cation-selective and should exhibit relatively low permeability to numerous vital negatively charged metabolites and high permeability to K+, a major charge carrier in cell– cell communication.

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Section: Discussionmentioning

confidence: 99%

Neurons and β-Cells of the Pancreas Express Connexin36, Forming Gap Junction Channels that Exhibit Strong Cationic Selectivity

Bukauskas

2012

J Membrane Biol

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“…Such computational tissues would be ideal media in which to store and manipulate the information used by morphogenetic fields. Given that many cell types are communicating electrically via membrane potential and highly-tunable electric synapses, gap junctions [88,481–483], there may not be any fundamental difference between the information-processing functions of neural networks and similar electrical dynamics in non-neural cells. Thus, cancer could be a regenerative response that cannot remember what target morphology is to be recognized as the “end of growth signal”, and a reprogramming solution could be sought in repairing the ability of cells to access the electrically-mediated memory of appropriate tissue organization and the cell behaviors that are needed to achieve that state.…”

Section: Future Prospects/speculationsmentioning

confidence: 99%

Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

Chernet¹,

Levin²

2014

J Clin Exp Oncol

137

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Cancer may be a disease of geometry: a misregulation of the field of information that orchestrates individual cells’ activities towards normal anatomy. Recent work identified molecular mechanisms underlying a novel system of developmental control: bioelectric gradients. Endogenous spatio-temporal differences in resting potential of non-neural cells provide instructive cues for cell regulation and complex patterning during embryogenesis and regeneration. It is now appreciated that these cues are an important layer of the dysregulation of cell: cell interactions that leads to cancer. Abnormal depolarization of resting potential (Vmem) is a convenient marker for neoplasia and activates a metastatic phenotype in genetically-normal cells in vivo. Moreover, oncogene expression depolarizes cells that form tumor-like structures, but is unable to form tumors if this depolarization is artificially prevented by misexpression of hyperpolarizing ion channels. Vmem triggers metastatic behaviors at considerable distance, mediated by transcriptional and epigenetic effects of electrically-modulated flows of serotonin and butyrate. While in vivo data on voltages in carcinogenesis comes mainly from the amphibian model, unbiased genetic screens and network profiling in rodents and human tissues reveal several ion channel proteins as bona fide oncogene and promising targets for cancer drug development. However, we propose that a focus on specific channel genes is just the tip of the iceberg. Bioelectric state is determined by post-translational gating of ion channels, not only from genetically-specified complements of ion translocators. A better model is a statistical dynamics view of spatial Vmem gradients. Cancer may not originate at the single cell level, since gap junctional coupling results in multi-cellular physiological networks with multiple stable attractors in bioelectrical state space. New medical applications await a detailed understanding of the mechanisms by which organ target morphology stored in real-time patterns of ion flows is perceived or mis-perceived by cells. Mastery of somatic voltage gradients will lead to cancer normalization or rebooting strategies, such as those that occur in regenerating and embryonic organs, resulting in transformative advances in basic biology and oncology.

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“…Changes in V mem of cells, such as cancer-associated depolarization, can trigger transcriptional changes by (1) regulating the movement of morphogens such as serotonin, calcium, and inositol triphosphate through gap junctions [116,117,[231][232][233][234][235], (2) controlling the import/export of small signaling molecules such as butyrate across membrane exchangers [208,[235][236][237][238], and (3) modulating the activity level of phosphatases such as PTEN [239][240][241][242]. Together, these transduction mechanisms convert an essentially biophysical state change into secondary messenger events that impact on transcriptional and epigenetic regulation of loci such as NODAL or SLUG which are important intermediate effectors for the cancer phenotype [238,243].…”

Section: Bioelectric States Control Cell Behaviormentioning

confidence: 99%

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

Moore

Walker

Levin

2017

Converg. Sci. Phys. Oncol.

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TOPICAL REVIEWCancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem IntroductionCancer is well-recognized not only as an extremely pernicious medical problem, but also as a group of phenomena deeply connected to the fundamental questions of evolution, multicellularity, pattern (disregulation, and the interplay between the genome and the environment [1,2]. Two fundamental paradigms currently divide the field. One is that cancer results from disorders of genetics: cancer cells are fundamentally broken due to genomic mutation or instability, and their clonal progeny form tumors and metastases. This view is sometimes called the SMT, somatic mutation theory [3][4][5]. A competing perspective is that of cancer as a circuit disease-a disorder of the complex biophysical, transcriptional, and epigenetic dynamics that regulate cellular state and the ability of cells to cooperate in vivo [6][7][8]. Under this view (sometimes called the tissue organization field theory or TOFT, [9,10]), cancer is akin to a traffic jam [11]-the problem is not a permanent discrete alteration within a founder cell and all of its clonal descendants, but an undesirable stable attractor in the complex network of controls that normally guides anatomical homeostasis [12].The relative merits of the two models have been discussed extensively [10,[13][14][15][16][17] AbstractThe current paradigm views cancer as arising clonally from a degradation of genetic information in single cells. A complementary perspective, originating at the dawn of modern developmental biology, is that cancer is the result of a system disorder of algorithms that normally orchestrate individual cell activities toward specific anatomical structures and away from tumorigenesis. A view of cancer as a disease of geometry focuses on the pathways that allow cells to cooperate to build and maintain large-scale anatomical patterning. Cancer may result when cells stop maintaining higher-order structures and reduce the boundary of their computational selves to a single-cell level, reverting to a unicellular lifestyle in which the rest of the organism is merely part of the environment at the expense of which all living things survive. While this view has been widely discussed, little progress has been made in providing a quantitative, mechanistic framework within which this perspective's specific and unique implications for treatment strategies can be tested and biomedically exploited. Here, we highlight two recent areas of progress which may facilitate much-needed progress on the cancer problem. First, we review the roles that endogenous bioelectrical networks, operating across many tissues in vivo, play as a medium of information processing in tumor suppression, progression, and reprogramming. Second, we provide a primer to the development of computational theory and tools for quantifying the information and causal control structures in cancer and other complex biological systems. Rigorous mathematical formalisms now exist to...

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Modulation of metabolic communication through gap junction channels by transjunctional voltage; synergistic and antagonistic effects of gating and ionophoresis

Cited by 41 publications

References 78 publications

Neurons and β-Cells of the Pancreas Express Connexin36, Forming Gap Junction Channels that Exhibit Strong Cationic Selectivity

Neurons and β-Cells of the Pancreas Express Connexin36, Forming Gap Junction Channels that Exhibit Strong Cationic Selectivity

Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

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