Gap junctions are specialized membrane domains composed of collections of channels that directly connect neighboring cells providing for the cell-to-cell diffusion of small molecules, including ions, amino acids, nucleotides, and second messengers. Vertebrate gap junctions are composed of proteins encoded by the "connexin" gene family. In most cases examined, connexins are modified post-translationally by phosphorylation. Phosphorylation has been implicated in the regulation of gap junctional communication at several stages of the connexin "lifecycle", such as the trafficking, assembly/disassembly, degradation, as well as, the gating of gap junction channels. Since connexin43 (Cx43) is widely expressed in tissues and cell lines, we understand the most about how it is regulated, and thus, connexin43 phosphorylation is a major focus of this review. Recent reports utilizing new methodologies combined with the latest genome information have shown that activation of several kinases including protein kinase A, protein kinase C, p34(cdc2)/cyclin B kinase, casein kinase 1, mitogen-activated protein (MAP) kinase and pp60(src) kinase can lead to phosphorylation at 12 of the 21 serine and two of the six tyrosine residues in the C-terminal region of connexin43. In several cases, use of site-directed mutants of these sites have shown that these specific phosphorylation events can be linked to changes in gap junctional communication.

Electrical synaptic transmission through gap junctions underlies direct and rapid neuronal communication in the CNS. The diversity of functional roles that electrical synapses have is perhaps best exemplified in the vertebrate retina, in which gap junctions are formed by each of the five major neuron types. These junctions are dynamically regulated by ambient illumination and by circadian rhythms acting through light-activated neuromodulators such as dopamine and nitric oxide, which in turn activate intracellular signalling pathways in the retina.The networks formed by electrically coupled neurons are plastic and reconfigurable, and those in the retina are positioned to play key and diverse parts in the transmission and processing of visual information at every retinal level.

Gap junctions are a unique type of intercellular junction found in most animal cell types. Gap junctions permit the intercellular passage of small molecules and have been implicated in diverse biological processes, such as development, cellular metabolism, and cellular growth control. In vertebrates, gap junctions are composed of proteins from the "connexin" gene family. The majority of connexins are modified posttranslationally by phosphorylation, primarily on serine amino acids; however, phosphotyrosine has also been detected in connexin from cells coexpressing nonreceptor tyrosine protein kinases. Connexins are targeted by numerous protein kinases, of which some have been identified: protein kinase C, mitogen-activated protein kinase, and the v-Src tyrosine protein kinase. Phosphorylation has been implicated in the regulation of a broad variety of connexin processes, such as the trafficking, assembly/disassembly, degradation, as well as the gating of gap junction channels. This review examines the consequences of connexin phosphorylation for the regulation of gap junctional communication.

Gap junction proteins, connexins, are dynamic polytopic membrane proteins that exhibit unprecedented short half-lives of only a few hours. Consequently, it is well accepted that in addition to channel gating, gap junctional intercellular communication is regulated by connexin biosynthesis, transport and assembly as well as the formation and removal of gap junctions from the cell surface. At least nine members of the 20-member connexin family are known to be phosphorylated en route or during their assembly into gap junctions. For some connexins, notably Cx43, evidence exists that phosphorylation may trigger its internalization and degradation. In recent years it has become apparent that the mechanisms underlying the regulation of connexin turnover are quite complex with the identification of many connexin binding molecules, a multiplicity of protein kinases that phosphorylate connexins and the involvement of both lysosomal and proteasomal pathways in degrading connexins. This paper will review the evidence that connexin phosphorylation regulates, stimulates or triggers gap junction disassembly, internalization and degradation.

In most multicellular organisms direct cell-cell communication is mediated by the intercellular channels of gap junctions. These channels allow the exchange of ions and molecules that are believed to be essential for cell signalling during development and in some differentiated tissues. Proteins called connexins, which are products of a multigene family, are the structural components of vertebrate gap junctions. Surprisingly, molecular homologues of the connexins have not been described in any invertebrate. A separate gene family, which includes the Drosophila genes shaking-B and l(1)ogre, and the Caenorhabditis elegans genes unc-7 and eat-5, encodes transmembrane proteins with a predicted structure similar to that of the connexins. shaking-B and eat-5 are required for the formation of functional gap junctions. To test directly whether Shaking-B is a channel protein, we expressed it in paired Xenopus oocytes. Here we show that Shaking-B localizes to the membrane, and that its presence induces the formation of functional intercellular channels. To our knowledge, this is the first structural component of an invertebrate gap junction to be characterized.

In the mammalian central nervous system (CNS), coupling of neurons by gap junctions (i.e., electrical synapses) and the expression of the neuronal gap junction protein, connexin 36 (Cx36), transiently increase during early postnatal development. The levels of both subsequently decline and remain low in the adult, confined to specific subsets of neurons. However, following neuronal injury [such as ischemia, traumatic brain injury (TBI), and epilepsy], the coupling and expression of Cx36 rise. Here we summarize new findings on the mechanisms of regulation of Cx36-containing gap junctions in the developing and mature CNS and following injury. We also review recent studies suggesting various roles for neuronal gap junctions and in particular their role in glutamate-mediated neuronal death.

Electrical synaptic transmission via gap junctions underlies direct and rapid neuronal communication in the central nervous system. The diversity of functional roles played by electrical synapses is perhaps best exemplified in the vertebrate retina, in which gap junctions are expressed by each of the five major neuronal types. These junctions are highly plastic; they are dynamically regulated by ambient illumination and circadian rhythms acting through light-activated neuromodulators. The networks formed by electrically coupled neurons provide plastic, reconfigurable circuits positioned to play key and diverse roles in the transmission and processing of visual information at every retinal level. Recent work indicates gap junctions also play a role in the progressive cell death and aberrant activity seen in various pathological conditions of the retina. Gap junctions thus form potential targets for novel neuroprotective therapies in the treatment of neurodegenerative retinal diseases such as glaucoma and ischemic retinopathies.

The presence of direct, cytoplasmatic, communication between neurons in the brain of vertebrates has been demonstrated a long time ago. These gap junctions have been characterized in many brain areas in terms of subunit composition, biophysical properties, neuronal connectivity patterns, and developmental regulation. Although interesting findings emerged, showing that different subunits are specifically regulated during development, or that excitatory and inhibitory neuronal networks exhibit various electrical connectivity patterns, gap junctions did not receive much further interest. Originally, it was believed that gap junctions represent simple passageways for electrical and biochemical coordination early in development. Today, we know that gap junction connectivity is tightly regulated, following independent developmental patterns for excitatory and inhibitory networks. Electrical connections are important for many specific functions of neurons, and are, for example, required for the development of neuronal stimulus tuning in the visual system. Here, we integrate the available data on neuronal connectivity and gap junction properties, as well as the most recent findings concerning the functional implications of electrical connections in the developing thalamus and neocortex.

Cell-cell communication via gap junctions regulates a wide range of physiological processes by enabling the direct intercellular electrical and chemical coupling. However, the in vivo distribution and function of gap junctions remain poorly understood, partly due to the lack of non-invasive tools with both cell-type specificity and high spatiotemporal resolution. Here we developed PARIS (pairing actuators and receivers to optically isolate gap junctions), a new fully genetically encoded tool for measuring the cell-specific gap junctional coupling (GJC). PARIS successfully enabled monitoring of GJC in several cultured cell lines under physiologically relevant conditions and in distinct genetically defined neurons in Drosophila brain, with ~10-sec temporal resolution and sub-cellular spatial resolution. These results demonstrate that PARIS is a robust, highly sensitive tool for mapping functional gap junctions and study their regulation in both health and disease.

Gap junctions are intercellular membrane channels consisting of connexin proteins, which contribute to direct cytoplasmic exchange of small molecules, substrates and metabolites between adjacent cells. These channels play important roles in neuronal differentiation, maintenance, survival and function. Gap junctions regulate differentiation of neurons from embryonic, neural and induced pluripotent stem cells. In addition, they control transdifferentiation of neurons from mesenchymal stem cells. The expression and levels of several connexins correlate with cell cycle changes and different stages of neurogenesis. Connexins such as Cx36, Cx45, and Cx26, play a crucial role in neuronal function. Several connexin knockout mice display lethal or severely impaired phenotypes. Aberrations in connexin expression is frequently associated with various neurodegenerative disorders. Gap junctions also act as promising therapeutic targets for neuronal regenerative medicine, because of their role in neural stem cell integration, injury and remyelination.

Gap junctions are essential channels of communication between cells including neurons in the central nervous system. These channels coordinate cell metabolic and electrical functions including such crucial ones for maintaining homeostasis as cell proliferation, differentiation, survival, and apoptosis. They create narrow passageways that allow rapid exchange of small molecules, ions, and secondary messengers between neighboring cells including the retina and optic nerve. Disruption in normal functioning of gap junctions may result in various neurodegenerative disorders. A comprehensive understanding of gap junction composition, function, and regulation is the key in determining novel approaches to neuroprotection and neuroregeneration. Here, we review the structure and the role of gap junctions in the retina and discuss the life cycle of connexins and their involvement in retinal neurodegenerations.

transmission between neurons. In the case of electrical synapses, neurons are coupled bidirectionally with each other through gap junctions and have a connected In the nervous system, a synapse is a structure that allows a neuron to exchange (receive or send) signals with another cell in its immediate vicinity. Synapses can be classified as either chemical or electrical, depending on the mechanism of signal transmission between neurons. In the case of electrical synapses, neurons are coupled bidirectionally with each other through gap junctions and have a In…

Electrical synapses formed by gap junctions are abundant in nervous systems and critical for brain function. They allow not only the exchange of ions, but also of metabolites and second messengers and have been implicated in the transmission of damage or death signals between cells. However, it was not known if they play a role in the processes that regulate neural ageing and lifespan. In my PhD project, I sought to explore if gap junctions affect ageing and lifespan using the roundworm Caenorhabditis elegans. Gap junctions are present in virtually all cells and tissues of C. elegans and are formed by twenty-five innexin genes encoding gap junction subunits. I assayed lifespan of loss-of-function mutants of most C. elegans innexins and discovered that innexins have a significant impact on lifespan, some leading to an extension of lifespan while others accelerate the ageing process and shorten lifespan. Specifically, null mutations in unc-9, the most widely expressed innexin in the nervous system, extended lifespan by up to thirty-five percent compared to wild-type. Its effect on longevity is likely due to the intercellular coupling provided by UNC-9, as loss of the UNC-9-regulating stomatin unc-1 extends lifespan in the same manner. In follow-up experiments, I used RNA interference to ask if UNC-9 acts in specific sets of cells to modulate longevity. Its removal from glutamatergic neurons led to an increase in lifespan, whereas I found no effects of unc-9 knock-down in GABAer

Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such as small molecules, substrates Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such as small molecules, substrates, and metabolites. Gap junctions were first described as close appositions alongside tight junctions, but based on electron microscopy studies, they were later renamed gap junctions to distinguish them from tight junctions. They bridge a 2-4 nm ga Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such as small molecules, substrates, and metabolites. Gap junctions were first described as close appositions alongside tight junctions, but based on electron microscopy studies, they were later renamed gap junctions to distinguish them from tight junctions. They bridge a 2-4 nm gap between cell membranes. Gap junctions use protein complexes known as connexons, composed of connexin proteins to connect one cell to another. Gap junction proteins include the more than 26 types of connexin, as well as at least 12 non-connexin components that make up the gap junction complex or nexus, including the tight junction protein ZO-1—a protein that holds membrane content together and adds structural clarity to a cell, sodium channels, and aquaporin. More gap junction proteins have become known due to the development of next-generation sequencing. Connexins were found to be structurally homologous between vertebrates and invertebrates but different in sequence. As a result, the term innexin is used to differentiate invertebrate connexins. There are more than 20 known innexins, along with unnexins in parasites and vinnexins in viruses. An electrical synapse is a gap junction that can transmit action potentials between neurons. Such synapses create bidirectional continuous-time electrical coupling between neurons. Connexon pairs act as generalized regulated gates for ions and smaller molecules between cells. Hemichannel connexons form channels to the extracellular environment. A gap junction is different from an ephaptic coupling that involves electrical signals external to the cells. Astrocytes An important feature of astrocytes is their high expression levels of the gap junction proteins connexin 30 (Cx30) and connexin 43 (Cx43). These proteins play crucial roles in regulating brain homeostasis through potassium buffering, intercellular communication, and nutrient transport. Connexins typically form gap junction channels that allow direct intercellular communication between astrocytes. However, they can also form hemichannels that facilitate the exchange of…