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"Gap"
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Gap-junction-mediated cell-to-cell communication
Cells of multicellular organisms need to communicate with each other and have evolved various mechanisms for this purpose, the most direct and quickest of which is through channels that directly connect the cytoplasms of adjacent cells. Such intercellular channels span the two plasma membranes and the intercellular space and result from the docking of two hemichannels. These channels are densely packed into plasma-membrane spatial microdomains termed “gap junctions” and allow cells to exchange ions and small molecules directly. A hemichannel is a hexameric torus of junctional proteins around an aqueous pore. Vertebrates express two families of gap-junction proteins: the well-characterized connexins and the more recently discovered pannexins, the latter being related to invertebrate innexins (“invertebrate connexins”). Some gap-junctional hemichannels also appear to mediate cell-extracellular communication. Communicating junctions play crucial roles in the maintenance of homeostasis, morphogenesis, cell differentiation and growth control in metazoans. Gap-junctional channels are not passive conduits, as previously long regarded, but use “gating” mechanisms to open and close the central pore in response to biological stimuli (e.g. a change in the transjunctional voltage). Their permeability is finely tuned by complex mechanisms that have just begun to be identified. Given their ubiquity and diversity, gap junctions play crucial roles in a plethora of functions and their dysfunctions are involved in a wide range of diseases. However, the exact mechanisms involved remain poorly understood.
Journal Article
Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease
Connexins are tetraspan transmembrane proteins that form gap junctions and facilitate direct intercellular communication, a critical feature for the development, function, and homeostasis of tissues and organs. In addition, a growing number of gap junction-independent functions are being ascribed to these proteins. The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional level, and undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability, and function. Here, we summarize these key regulatory events, with emphasis on how these affect connexin multifunctionality in health and disease.
Journal Article
Structure of native lens connexin 46/50 intercellular channels by cryo-EM
Gap junctions establish direct pathways for cell-to-cell communication through the assembly of twelve connexin subunits that form intercellular channels connecting neighbouring cells. Co-assembly of different connexin isoforms produces channels with unique properties and enables communication across cell types. Here we used single-particle cryo-electron microscopy to investigate the structural basis of connexin co-assembly in native lens gap junction channels composed of connexin 46 and connexin 50 (Cx46/50). We provide the first comparative analysis to connexin 26 (Cx26), which—together with computational studies—elucidates key energetic features governing gap junction permselectivity. Cx46/50 adopts an open-state conformation that is distinct from the Cx26 crystal structure, yet it appears to be stabilized by a conserved set of hydrophobic anchoring residues. ‘Hot spots’ of genetic mutations linked to hereditary cataract formation map to the core structural–functional elements identified in Cx46/50, suggesting explanations for many of the disease-causing effects.
Cryo-electron microscopy structures of connexin channels composed of connexin 46 and connexin 50 in an open-state reveal features that govern permselectivity and the location of mutated residues linked to herediatry cataracts.
Journal Article
Why Ethical Consumers Don't Walk Their Talk: Towards a Framework for Understanding the Gap Between the Ethical Purchase Intentions and Actual Buying Behaviour of Ethically Minded Consumers
Despite their ethical intentions, ethically minded consumers rarely purchase ethical products (Auger and Devinney: 2007, Journal of Business Ethics 76, 361-383). This intentions-behaviour gap is important to researchers and industry, yet poorly understood (Belk et al.: 2005, Consumption, Markets and Culture 8(3), 275-289). In order to push the understanding of ethical consumption forward, we draw on what is known about the intention— behaviour gap from the social psychology and consumer behaviour literatures and apply these insights to ethical consumerism. We bring together three separate insights — implementation intentions (Gollwitzer: 1999, American Psychologist 54(7), 493-503), actual behavioural control (ABC) (Ajzen and Madden: 1986, Journal of Experimental Social Psychology 22, 453-474; Sheeran et al.: 2003, Journal of Social Psychology, 42, 393-410) and situational context (SC) (Belk: 1975, Journal of Consumer Research 2, 157— 164) — to construct an integrated, holistic conceptual model of the intention— behaviour gap of ethically minded consumers. This holistic conceptual model addresses significant limitations within the ethical consumerism literature, and moves the understanding of ethical consumer behaviour forward. Further, the operationalisation of this model offers insight and strategic direction for marketing managers attempting to bridge the intention-behaviour gap of the ethically minded consumer.
Journal Article
Cellular mechanisms of synchronized rhythmic burst generation in the ventromedial hypothalamus
The ventromedial hypothalamus (VMH) plays an important role in feeding behavior and control of the sympathetic nervous system (SNS). The VMH includes a group of neurons that exhibit strong synchronized rhythmic burst firing (so-called VMH oscillation). This VMH oscillation is glucose inhibited, responsive to feeding-related peptides, and is functionally coupled to outputs of the SNS. However, the details of its rhythm generation and synchronization mechanisms are unknown. In the present study, we investigated cellular mechanisms of VMH oscillation by means of electrophysiological recordings and calcium imaging in juvenile rat slice preparations including the VMH. In the electrophysiological study, we performed membrane potential recording from neurons in the vicinity of pipettes for field potential recording. We found that the rhythmic bursts in the VMH were preserved in low Ca
2+
/high Mg
2+
synaptic transmission blockade solution. During membrane hyperpolarization by current injection, the action potential was largely inhibited, but fluctuation of the membrane potential remained with a frequency similar to that at resting potential level. The electric VMH oscillation disappeared after application of either a gap junction blocker, carbenoxolone (100 µM), or a persistent sodium channel blocker, riluzole (20 µM). Membrane potentials and input resistances of rhythmic burst neurons in the VMH were not significantly changed during these manipulations. A calcium imaging study revealed that all VMH cells exhibiting synchronized rhythmic activity detected by intracellular calcium increases were silenced following the application of carbenoxolone. These results suggest that VMH oscillation arises from the activation of persistent sodium channels and coupling via gap junctions.
Journal Article
Intercalated discs: cellular adhesion and signaling in heart health and diseases
Intercalated discs (ICDs) are highly orchestrated structures that connect neighboring cardiomyocytes in the heart. Three major complexes are distinguished in ICD: desmosome, adherens junction (AJ), and gap junction (GJ). Desmosomes are major cell adhesion junctions that anchor cell membrane to the intermediate filament network; AJs connect the actin cytoskeleton of adjacent cells; and gap junctions metabolically and electrically connect the cytoplasm of adjacent cardiomyocytes. All these complexes work as a single unit, the so-called area composita, interdependently rather than individually. Mutation or altered expression of ICD proteins results in various cardiac diseases, such as ARVC (arrhythmogenic right ventricular cardiomyopathy), dilated cardiomyopathy, and hypotrophy cardiomyopathy, eventually leading to heart failure. In this article, we first review the recent findings on the structural organization of ICD and their functions and then focus on the recent advances in molecular pathogenesis of the ICD-related heart diseases, which include two major areas: i) the ICD gene mutations in cardiac diseases, and ii) the involvement of ICD proteins in signal transduction pathways leading to myocardium remodeling and eventual heart failure. These major ICD-related signaling pathways include Wnt/β-catenin pathway, p38 MAPK cascade, Rho-dependent serum response factor (SRF) signaling, calcineurin/NFAT signaling, Hippo kinase cascade, etc., which are differentially regulated in pathological conditions.
Journal Article
Auxiliary trafficking subunit GJA1-20k protects connexin-43 from degradation and limits ventricular arrhythmias
Connexin-43 (Cx43) gap junctions provide intercellular coupling, which ensures rapid action potential propagation and synchronized heart contraction. Alterations in Cx43 localization and reductions in gap junction coupling occur in failing hearts, contributing to ventricular arrhythmias and sudden cardiac death. Recent reports have found that an internally translated Cx43 isoform, GJA1-20k, is an auxiliary subunit for the trafficking of Cx43 in heterologous expression systems. Here, we have created a mouse model by using CRISPR technology to mutate a single internal translation initiation site in Cx43 (M213L mutation), which generates full-length Cx43, but not GJA1-20k. We found that GJA1M213L/M213L mice had severely abnormal electrocardiograms despite preserved contractile function, reduced total Cx43, and reduced gap junctions, and they died suddenly at 2 to 4 weeks of age. Heterozygous GJA1M213L/WT mice survived to adulthood with increased ventricular ectopy. Biochemical experiments indicated that cytoplasmic Cx43 had a half-life that was 50% shorter than membrane-associated Cx43. Without GJA1-20k, poorly trafficked Cx43 was degraded. The data support that GJA1-20k, an endogenous entity translated independently of Cx43, is critical for Cx43 gap junction trafficking, maintenance of Cx43 protein, and normal electrical function of the mammalian heart.
Journal Article
Hexagonal boron nitride is an indirect bandgap semiconductor
Hexagonal boron nitride is a wide bandgap semiconductor with very high thermal and chemical stability that is used in devices operating under extreme conditions. The growth of high-purity crystals has recently revealed the potential of this material for deep ultraviolet emission, with intense emission around 215 nm. In the last few years, hexagonal boron nitride has been attracting even more attention with the emergence of two-dimensional atomic crystals and van der Waals heterostructures, initiated with the discovery of graphene. Despite this growing interest and a seemingly simple structure, the basic questions of the bandgap nature and value are still controversial. Here, we resolve this long-debated issue by demonstrating evidence for an indirect bandgap at 5.955 eV by means of optical spectroscopy. We demonstrate the existence of phonon-assisted optical transitions and we measure an exciton binding energy of about 130 meV by two-photon spectroscopy.
Scientists resolve the long-debated issue of the nature and value of the bandgap in hexagonal boron nitride by providing evidence for an indirect bandgap at 5.955 eV and an exciton binding energy of about 130 meV by means of optical spectroscopy.
Journal Article
Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress
In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled neurodegeneration in glaucoma, the world’s leading cause of irreversible blindness, and measured how metabolites mobilize through astrocyte gap junctions composed of connexin 43 (Cx43). We elevated intraocular pressure in one eye and determined how astrocyte-derived metabolites in the contralateral optic projection responded. Remarkably, astrocyte networks expand and redistribute metabolites along distances even 10 mm in length, donating resources from the unstressed to the stressed projection in response to intraocular pressure elevation. While resource donation improves axon function and visual acuity in the directly stressed region, it renders the donating tissue susceptible to bioenergetic, structural, and physiological degradation. Intriguingly, when both projections are stressed in a WT animal, axon function and visual acuity equilibrate between the two projections even when each projection is stressed for a different length of time. This equilibration does not occur when Cx43 is not present. Thus, Cx43-mediated astrocyte metabolic networks serve as an endogenous mechanism used to mitigate bioenergetic stress and distribute the impact of neurodegenerative disease processes. Redistribution ultimately renders the donating optic nerve vulnerable to further metabolic stress, which could explain why local neurodegeneration does not remain confined, but eventually impacts healthy regions of the brain more broadly.
Journal Article