Gap junctions: structure and function (Review)

Gap junctions are plasma membrane spatial microdomains constructed of assemblies of channel proteins called connexins in vertebrates and innexins in invertebrates. The channels provide direct intercellular communication pathways allowing rapid exchange of ions and metabolites up to approximately 1 kD in size. Approximately 20 connexins are identified in the human or mouse genome, and orthologues are increasingly characterized in other vertebrates. Most cell types express multiple connexin isoforms, making likely the construction of a spectrum of heteromeric hemichannels and heterotypic gap junctions that could provide a structural basis for the charge and size selectivity of these intercellular channels. The precise nature of the potential signalling information traversing junctions in physiologically defined situations remains elusive, but extensive progress has been made in elucidating how connexins are assembled into gap junctions. Also, participation of gap junction hemichannels in the propagation of calcium waves via an extracellular purinergic pathway is emerging. Connexin mutations have been identified in a number of genetically inherited channel communication-opathies. These are detected in connexin 32 in Charcot Marie Tooth-X linked disease, in connexins 26 and 30 in deafness and skin diseases, and in connexins 46 and 50 in hereditary cataracts. Biochemical approaches indicate that many of the mutated connexins are mistargeted to gap junctions and/or fail to oligomerize correctly into hemichannels. Genetic ablation approaches are helping to map out a connexin code and point to specific connexins being required for cell growth and differentiation as well as underwriting basic intercellular communication.     

Gap junctions: structure and function (Review)

Gap junctions are plasma membrane spatial microdomains constructed of assemblies of channel proteins called connexins in vertebrates and innexins in invertebrates. The channels provide direct intercellular communication pathways allowing rapid exchange of ions and metabolites up to ~1 kD in size. Approximately 20 connexins are identified in the human or mouse genome, and orthologues are increasingly characterized in other vertebrates. Most cell types express multiple connexin isoforms, making likely the construction of a spectrum of heteromeric hemichannels and heterotypic gap junctions that could provide a structural basis for the charge and size selectivity of these intercellular channels. The precise nature of the potential signalling information traversing junctions in physiologically defined situations remains elusive, but extensive progress has been made in elucidating how connexins are assembled into gap junctions. Also, participation of gap junction hemichannels in the propagation of calcium waves via an extracellular purinergic pathway is emerging. Connexin mutations have been identified in a number of genetically inherited channel communication-opathies. These are detected in connexin 32 in Charcot Marie Tooth-X linked disease, in connexins 26 and 30 in deafness and skin diseases, and in connexins 46 and 50 in hereditary cataracts. Biochemical approaches indicate that many of the mutated connexins are mistargeted to gap junctions and/or fail to oligomerize correctly into hemichannels. Genetic ablation approaches are helping to map out a connexin code and point to specific connexins being required for cell growth and differentiation as well as underwriting basic intercellular communication.     

Enteroendocrine cells, their structure and function

The modern classification of the gastroenteropancreatic endocrine system (GEPES) is presented. Qualitative and quantitative composition of the entero-endocrine system (EES) included in the GEPES is considered, as well as functional role of every type of the cells. The literature data are summarized and the morphology at the light optic and electron microscopic levels of the endocrine cells and the peptidergic nerves of the intestine is demonstrated. The existing methods for investigation of the EES endocrine cells and for the whole neuroendocrine complex of the gastro-intestinal tract taken together are analysed.     

Morpho-functional correlations of the structure of bone cells and adjoining bone matrix in the developing bone

By means of scanning and transmissive electron microscopy methods structure of the developing bone has been studied. Interconnection of the cell structure and spatial organization of the adjoining matrix has been demonstrated. On the surface of the growing bone not only forming areas have been revealed, where under osteoblasts at various functional states, osteoid layer is determined, but also areas of resorption and completed osteogenesis. This demonstrates an interrupted character of osteogenesis at modelling. At the same time for the remodelling process presence of erosive lacunae is specific; they are filled with a newly deposited collagenous matrix. Therefore, it is possible to suppose that formation of the bone as an organ during the postnatal development includes in itself both mechanisms supporting its form at outgrowth of the osseous matrix volume (modeling) and its continuous rearrangement and adaptation to real conditions of functioning (remodelling).     

V-ATPase:结构、功能及其在肿瘤细胞中的作用

真核细胞膜及管泡细胞器膜上广泛分布一种与H^ 主动转运有关的蛋白——V-ATPase。V-ATPase的结构由跨膜的V0和细胞质内的V1两个亚单位组成,前者为H^ 提供通道,后者能分解ATP,为逆浓度梯度转运H^ 提供能量。V0和V1只有在聚合时,V-ATPase全酶才有功能。肿瘤细胞中V-ATPase的过度表达或过度活跃,遏制了由酵解增强乳酸聚集导致的细胞内酸化趋势,使细胞避免了凋亡的命运。而H^ 排至细胞外,改变蛋白水解酶的活性,使细胞外基质分解增强,细胞更有侵袭力。肿瘤细胞的V-ATPase可望成为抑制细胞增生、扩散的有效靶点。     

Significance of input correlations in striatal function

The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia.     

Cryo-electron tomography of cells: connecting structure and function

Cryo-electron tomography (cryo-ET) allows the visualization of cellular structures under close-to-life conditions and at molecular resolution. While it is inherently a static approach, yielding structural information about supramolecular organization at a certain time point, it can nevertheless provide insights into function of the structures imaged, in particular, when supplemented by other approaches. Here, we review the use of experimental methods that supplement cryo-ET imaging of whole cells. These include genetic and pharmacological manipulations, as well as correlative light microscopy and cryo-ET. While these methods have mostly been used to detect and identify structures visualized in cryo-ET or to assist the search for a feature of interest, we expect that in the future they will play a more important role in the functional interpretation of cryo-tomograms.     

Migrating cells retain gap junction plaque structure and function

Cell migration is an essential process in organ development, differentiation, and wound healing, and it has been hypothesized that gap junctions play a pivotal role in these cell processes. However, the changes in gap junctions and the capacity for cell communication as cells migrate are unclear. To monitor gap junction plaques during cell migration, adrenocortical cells were transfected with cDNA encoding for the connexin 43-green fluorescent protein. Time-lapse imaging was used to analyze cell movements and concurrent gap junction plaque dynamics. Immunocytochemistry was used to analyze gap junction morphology and distribution. Migration was initiated by wounding the cell monolayer and diffusional coupling was demonstrated by monitoring Lucifer yellow dye transfer and fluorescence recovery after photobleaching (FRAP) in cells at the wound edge and in cells located some distance from the wound edge. Gap junction plaques were retained at sites of contact while cells migrated in a "sheet-like" formation, even when cells dramatically changed their spatial relationship to one another. Consistent with this finding, cells at the leading edge retained their capacity to communicate with contacting cells. When cells detached from one another, gap junction plaques were internalized just prior to cell process detachment. Although gap junction plaque internalization clearly was a method of gap junction removal during cell separation, cells retained gap junction plaques and continued to communicate dye while migrating.     

How structure determines correlations in neuronal networks

Networks are becoming a ubiquitous metaphor for the understanding of complex biological systems, spanning the range between molecular signalling pathways, neural networks in the brain, and interacting species in a food web. In many models, we face an intricate interplay between the topology of the network and the dynamics of the system, which is generally very hard to disentangle. A dynamical feature that has been subject of intense research in various fields are correlations between the noisy activity of nodes in a network. We consider a class of systems, where discrete signals are sent along the links of the network. Such systems are of particular relevance in neuroscience, because they provide models for networks of neurons that use action potentials for communication. We study correlations in dynamic networks with arbitrary topology, assuming linear pulse coupling. With our novel approach, we are able to understand in detail how specific structural motifs affect pairwise correlations. Based on a power series decomposition of the covariance matrix, we describe the conditions under which very indirect interactions will have a pronounced effect on correlations and population dynamics. In random networks, we find that indirect interactions may lead to a broad distribution of activation levels with low average but highly variable correlations. This phenomenon is even more pronounced in networks with distance dependent connectivity. In contrast, networks with highly connected hubs or patchy connections often exhibit strong average correlations. Our results are particularly relevant in view of new experimental techniques that enable the parallel recording of spiking activity from a large number of neurons, an appropriate interpretation of which is hampered by the currently limited understanding of structure-dynamics relations in complex networks.     

Effects of profilin and profilactin on actin structure and function in living cells

Previous studies have yielded conflicting results concerning the physiological role of profilin, a 12-15-kD actin- and phosphoinositide-binding protein, as a regulator of actin polymerization. We have addressed this question by directly microinjecting mammalian profilins, prepared either from an E. coli expression system or from bovine brain, into living normal rat kidney (NRK) cells. The microinjection causes a dose-dependent decrease in F-actin content, as indicated by staining with fluorescent phalloidin, and a dramatic reduction of actin and alpha-actinin along stress fibers. In addition, it has a strong inhibitory effect toward the extension of lamellipodia. However, the injection of profilin causes no detectable perturbation to the cell-substrate focal contact and no apparent depolymerization of filaments in either the nonlamellipodial circumferential band or the contractile ring of dividing cells. Furthermore, cytokinesis of injected cells occurs normally as in control cells. In contrast to pure profilin, high-affinity profilin-actin complexes from brain induce an increase in total cellular F-actin content and an enhanced ruffling activity, suggesting that the complex may dissociate readily in the cell and that there may be multiple states of profilin that differ in their ability to bind or release actin molecules. Our results indicate that profilin and profilactin can function as effective regulators for at least a subset of actin filaments in living cells.     

Ultrastructure of muscle cells from a few selected turbellarians: possible correlations between form and function

A comparative ultrastructural study of muscle cells from several turbellarian species revealed a basic smooth type of construction, with thick and thin myofilaments. However, the distribution of contractile elements, "dense bodies", smooth reticulum, mitochondria, as well as junctional specializations was found to vary within different systems. This variability is probably related to greater or lesser physical demands on the musculature. From a mechanical viewpoint, the most ‘powerful’ muscular system studied was represented by the pharyngeal bulb of Geocentrophora applanata, in which muscle fibers were organized into a compact, square reticulum, hemidesmosomes occurred in large numbers, and myofilaments were grouped in patches reminiscent of A and I bands of striated muscles. At the other extreme, muscular fibrils of the catenulids studied were thin and regularly spaced along the body wall, and the branched ends of radial myofibrils in the parenchyma were connected to the epithelial layer. This revised version was published online in July 2006 with corrections to the Cover Date.