Gap junctions

Electrical coupling through gap junctions constitutes a mode of signal transmission between neurons (electrical synaptic transmission). Originally discovered in invertebrates and in lower vertebrates, electrical synapses have recently been reported in immature and adult mammalian nervous systems. This has renewed the interest in understanding the role of electrical synapses in neural circuit function and signal processing. The present review focuses on the role of gap junctions in shaping the dynamics of neural networks by forming electrical synapses between neurons. Electrical synapses have been shown to be important elements in coincidence detection mechanisms and they can produce complex input-output functions when arranged in combination with chemical synapses. We postulate that these synapses may also be important in redefining neuronal compartments, associating anatomically distinct cellular structures into functional units. The original view of electrical synapses as static connecting elements in neural circuits has been revised and a considerable amount of evidence suggests that electrical synapses substantially affect the dynamics of neural circuits.     

Gap junctions and cancer: implications and perspectives

Gap junctions are made of intercellular channels which permit the diffusion from cytoplasm to cytoplasm of small hydrophilic molecules (<1,200 Da) such as ions, sugars, amino acids, nucleotides, second messengers (calcium, inositol triphosphate, etc.). Since their discovery in the early sixties, several groups have described the loss of their function in cancer cells. The accumulation of such data led to the hypothesis that gap junctions are involved in the carcinogenesis process. This assumption has been confirmed by data establishing that gap junctional intercellular communication is inhibited by most of the tumor promoters and that the restoration of such a communication, by transfection of cDNAs encoding gap junction proteins (connexins), inhibits the aberrant growth rates of tumorigenic cells. Despite these important informations, several fundamental questions remain still open. First, we do not know how gap junctions mediate such a tumor suppressor effect and whether it may depend either on the cell type or on the connexin type. Moreover, most of the data concerning a possible involvement of gap junctions in carcinogenesis have been obtained from in vitro and animal models. The very few results which have been currently collected from human tumors are not sufficient to have a clear idea concerning the real involvement of gap junctions in sporadic human cancers. These points as well as other unresolved questions about the role of gap junctional intercellular communication in carcinogenesis are mentioned. To bring some answers, some prospects are proposed with the objective to use gap junctions for increasing the effect of anticancer therapies.     

Gap junctions and tumour progression

Gap junctional intercellular communication has been implicated in growth control and differentiation. The mechanisms by which connexins, the gap junction proteins, act as tumor suppressors are unclear. In this review, several different mechanisms are considered. Since transformation results in a loss of the differentiated state, one mechanism by which gap junctions may control tumour progression is to promote or enhance differentiation. Processes of differentiation and growth control are mediated at the genetic level. Thus, an alternative or complimentary mechanism of tumour suppression could involve the regulation of gene expression by connexins and gap junctional coupling. Finally, gap junction channels form a conduit between cells for the exchange of ions, second messengers, and small metabolites. It is clear that the sharing of these molecules can be rather selective and may be involved in growth control processes. In this review, examples will be discussed that provide evidence for each of these mechanisms. Taken together, these findings point to a variety of mechanims by which connexins and the gap junction channels that they form may control tumour progression.     

细胞缝隙连接与心血管疾病

目录一、细胞缝隙连接的形态和结构二、细胞缝隙连接的功能　 (一 )参与信息的传递及神经冲动的传导　 (二 )协调细胞间活动的一致性　 (三 )参与细胞的分化生长与发育　 (四 )缓冲毒性化学物质的毒害作用　 (五 )通过周围细胞滋养受损细胞　 (六 )参与局部的代谢功能三、细胞缝隙连接蛋白功能的调节四、缝隙连接和心血管疾病　 (一 )心律失常　 (二 )动脉粥样硬化　 (三 )先天性心脏病　 (四 )缺血性心脏病　 (五 )心肌病细胞间通讯是一个在进化上很古老的功能 ,细胞间的通讯方式可分为间接与直接方式。以体循环远程分泌、旁分泌或自分泌方…     

Gap junctions between pinealocytes

Summary The intercellular junctions between the pinealocytes of male rats were investigated by freeze-fracture and conventional electron microscopy.Our findings reveal that the intercellular contacts between pineal cells, formerly described as zonulae adhaerentes or zonulae occludentes, are in fact gap junctions which are difficult to characterize in thin sections due to their peculiar geometrical arrangement, which is in the form of fenestrated communicating zonules.The arrangement of these communicating zonules around rudimentary lumina of pineal clusters and rare transitions between tight and gap junctions may point to phylogenetic transformations of occluding into communicating zonules, corresponding with the change of the pineal gland from a sensory to a secretory organ. Alternatively, these tight-to-gap junctional transitions may reflect the periodic (circadian or seasonal) activity of the pineal gland.These Studies were supported by the German Research Foundation within the SFB 90 Cardiovasculäres System     

Gap junctions: towards a molecular structure

Gap junctions are ubiquitous plasma membrane specializations that allow cells to exchange small molecules and ions directly. The isolation, biochemical characterization and molecular cloning of the major protein of rat liver gap junctions lead to a clearer view of these membrane zones that allow cells to ‘talk’ to each other and co-ordinate their activities in tissues and organs.     

Connexins: functions without junctions

Emerging studies indicate that connexins have activities completely unrelated to gap junctions and, conversely, that non-connexin proteins can form gap junction channels.     

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.     

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 as electrical synapses

Gap junctions are the morphological substrate of one class of electrical synapse. The history of the debate on electrical vs. chemical transmission is instructive. One lesson is that Occam’s razor sometimes cuts too deep; the nervous system does its operations in a number of different ways and a unitarian approach can lead one astray. Electrical synapses can do many things that chemical synapses can do, and do them just as slowly. More intriguing are the modulatory actions that chemical synapses can have on electrical synapses. Voltage dependence provides an important window on structure function relations of the connexins, even where the dependence may have no physiological role. The new molecular approaches will greatly advance our knowledge of where gap junctions occur and permit experimental manipulation with high specificity.     

Gap junctions between guinea-pig pinealocytes

Summary In accordance with previous results in rats, belt-like arrangements of fenestrated gap junctions have been found around the collicular segments of pineal cells in the guinea pig. In addition, macular interpinealocyte gap junctions have been observed in this species.S.-K. Huang was a recipient of a Humboldt Foundation fellowship.     

Gap junctions in excitable cells

Gap junction channels are an integral part of the conduction or propagation of an action potential from cell to cell. Gap junctions have rather unique gating and permeability properties which permit the movement of molecules from cell to cell. These molecules may not be directly linked to action potentials but can alter nonjunctional processes within cells, which in turn can affect conduction velocity. The data described in this review reveal that, for the majority of excitable cells, there are two limiting factors, with respect to gap junctions, that affect the conduction/propagation of action potentials. These are (1) the total number of channels and (2) the selective permeability of the channels. Interestingly, voltage dependence and the time course of voltage inactivation (kinetics) are not rate limiting steps under normal physiological conditions for any of the connexins studied so far. Only specialized rectifying electrical synapses utilize strong voltage dependence and rapid kinetics to permit or deny the continued propagation of an action potential.     

Special-interest subgroups at the ASCB: Gap junctions

The annual meeting of the American Society for Cell Biology (ASCB) is a large and diverse gathering. At last year's meeting**The American Society for Cell Biology 38th Annual Meeting, San Francisco, USA; 12-16 December, 1998. Program chair: Jennifer Lippincott-Schwartz., there were over 8000 attendees, and the topics discussed covered many areas of cell biology. It would be impossible to cover the entire meeting within a trends in CELL BIOLOGY report, so instead we are focusing on an aspect of it that provided some of the most interesting and fruitful discussions. On Saturday afternoon, before the main symposia began, there were 11 special-interest subgroup meetings. The atmosphere at these meetings was informal, and they encouraged open and frank discussion of data and issues. This report provides a brief summary of the discussions at seven of the special-interest subgroup meetings.     

Gap junctions in sea anemone, Nematostella vectensis, embryo

Gap junctions (GJs) are composed of membrane proteins that form channels connecting the cytoplasm of adjacent cells and permeable to ions and small molecules. They are considered to be the main or only type of intercellular channels and a universal feature of all multicellular animals (Metazoa). Till recently, sea anemones and corals (Anthozoa, Cnidaria) appeared to be an exception from this rule. There were no structural or physiological data supporting the presence of GJ in Anthozoa. For some time no genes homologous to GJ proteins (connexins or pannexins) were detected in sea anemone Nematostella vectensis (Cnidaria, Anthozoa) or other Anthozoa genomes. Recently, pannexin homolog was found in Nematostella. Our intracellular recordings demonstrate electrical coupling between blastomeres in embryos at the 8-cells stage. At the same time, carboxyfluorescein fluorescent dye did not diffuse between electrically coupled cells, which excludes the possibility that the observed electrical coupling is mediated by incomplete cytoplasm separation during the cleavage. These data support the idea that GJ are ubiquitous for Metazoa, and pannexins are universal GJ proteins.     

Gap junctions in hemodichorial and hemotrichorial placentae

Summary Gap junctions were found to be a constant feature of chorioallantoic placentae with two or three trophoblastic layers. The gap junctions connect layers I and II in hemodichorial and layers II and III in hemotrichorial placentae. Although the gap junctions vary in form and in the packing density of membrane-associated particles, they cover an extensive surface area in all species examined. The gap junctions always connect adjacent membranes of two trophoblastic layers, which show no evidence of micropinocytotic activity; at least one of these trophoblastic layers is syncytial. It is therefore concluded that the gap junctions play an important role in diaplacental transport. We consider that gap junctions act as molecular sieves, resulting in limitations in the transport of large molecules. The passage of small molecules, on the contrary, would be facilitated by the gap junctions.With the support of the Deutsche ForschungsgemeinschaftDedicated to Prof. Wolfgang Bargmann on his 70. birthdayWe are very grateful to Mrs. B. Brühl, I. Stenull and cand. med. P. Zahn for technical assisstence.We also gratefully acknowledge Prof. Dr. R. Taugner for helping us with freeze-fracturing