In a healthy organism, the processes of cellular growth and differentiation are tightly controlled, but in the pathological state, are uncoupled in such a way as to result in further damage-causing signals, or the growth of the malfunctioning cells. Proliferation of damaged or malfunctioning cells is often a key factor in the generation of disorders such as cancer , infectious diseases, inflammation, arteriosclerosis, arthritis , and neurodegenerative diseases.
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Signaling Through Cell Adhesion Molecules - Jun-Lin Guan - Google книги
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Signal Transduction Signal transduction also known as cell signaling is the transmission of molecular signals from a cell's exterior to its interior. Signal Transduction Pathways Transmission is continued either by a series of biochemical changes within the cell or by modification of the cell membrane potential by the movement of ions in or out of the cell. Interestingly, syntenin Sdcbp , identified in our Y2H screen black line color , directly interacts with the vesicle associated membrane protein Vamp2 also known as synaptobrevin 2 , identified by the BioID-assay orange line color which in turn interacts with the vesicle-associated membrane protein-associated protein A Vapa and B Vapb.
Building on the syntenin and Vamp2 interaction data, we studied their colocalization with CAR using immunofluorescence staining of cultured hippocampal neurons. For CAR channel 1 and syntenin channel 2 we measured tM1 0.
Taken together, we confirmed the interaction of CAR with postsynaptic proteins and uncovered new interactions of CAR with proteins of the presynapse — in particular those related to vesicle exocytosis. CAR is crucial for normal embryonic development and electrical conductance in the adult heart. Here we describe a novel role of CAR in neuronal cell-cell communication using a conditional knockout approach to exclusively study the role of CAR in the postnatal brain. Firstly, neuronal deletion of CAR at early postnatal stages enhances synaptic transmission and LTP as well as the probability of synaptic vesicle exocytosis and the speed of endocytosis.
Secondly, our data on synaptic protein expression and CAR distribution in synaptic membrane fractions extend previous work that attributed a primary postsynaptic function of CAR Additionally, in the hippocampus of CAR KO animals we find a specific upregulation of Syt2, a protein crucial for calcium induced exocytosis and, possibly, also for endocytic recycling 48 , 49 , Thus, our data extend the role of CAR in the adult brain with a novel role at the presynapse in vivo.
Cell adhesion proteins are important for neurite outgrowth and neuronal cell-cell contact formation during brain development 3 , 51 , Dendrite arborization and morphology of synapses, as well as the ratio of inhibitory to excitatory neurons are unchanged in CAR KO brains upon CAR deletion from the early postnatal stage. This lack of morphological change in the adult animal parallels our previous findings in the inducible heart specific CAR KO mice which display proper cardiac cell contacts We suggest that early postnatal elimination of CAR does not affect preexisting cell adhesions in either tissue.
Unlike other IgSF members, CAR is largely dispensable in the developing brain, as animals deficient for CAR in all tissues but the heart survive without an obvious phenotype Thus, the enhanced synaptic transmission most likely results from a primary function of CAR in the mature neuron and is not secondary to developmental defects. These CAR-mediated changes in synaptic function does not result in changes in the behavior tests, in contrast, when CAR is knocked out in early embryonic stages the deficiency leads to sex specific behavioral changes restricted to females only Syntenin is a scaffold protein, which interacts with cell adhesion molecules and synaptic proteins.
It contributes to the molecular organization of the active zone by interacting with CAST1, a protein of the cytomatrix in the active zone Additionally, the interaction of syntenin with ephrin-B1 and ephrin-B2 contributes to the development of the presynapse Therefore, we suggest that syntenin localizes CAR at the active zone and mediates its effect on vesicle release. Indeed, a similar increase in neurotransmitter release as documented in the CAR knockout has been observed in animals deficient in the syntenin binding protein CAST Furthermore, syntenin, as well as the CAR binding protein Pick1 interact with postsynaptic proteins such as glutamate receptors, participating in their targeted distribution at the synapse Loss of CAR could lead to an imbalance in Pick1 and syntenin function at the postsynaptic side with altered compartmentalization of glutamate receptors - the receptors that facilitates LTP NCAM is involved in vesicle mobilization and cycling through the regulation of the myosin light chain kinase signaling 10 , Alpha-neurexin localizes calcium channels to sites of vesicle release Therefore, we suggest that CAR predominantly acts on the presynaptic side at the level of the individual synapse, based on our findings that in CAR KO mice, synapse number, vesicle density and all other morphological parameters except for the vesicle number near the active zone was normal.
This is supported by co-localization of CAR with several proteins crucial for vesicle exo- and endocytosis and a specific upregulation of Syt2 expression in CAR KO neurons. Syt2 is a structural and functional homologue of Syt1 and both proteins are calcium sensors, which trigger calcium-dependent vesicle exocytosis 44 , 65 , They help to position vesicles adjacent to calcium channels, which affects priming and stabilization of the primed pool 67 , Syt1 is primarily expressed in the forebrain, while Syt2 expression is mainly restricted to the caudal regions of the brain and largely suppressed in hippocampus and cortex 69 , As direct effects of CAR on the regulation of gene expression have so far not been described, increased Syt2 levels are likely secondary effects reflecting altered vesicle mobility or priming and might contribute to improved transmitter release and thus synaptic strength.
Our data suggest a novel predominantly presynaptic function of CAR. Feedback signaling from the post- to the presynapse has previously been reported for the cell adhesion proteins neurexin and cadherin 71 , 72 and synCAM provides an example for transsynaptic homodimerization Our BioID approach extends the synaptic proteome and is consistent with a role of CAR homo- or heterodimers as additional links across the synaptic cleft. In summary, we show that CAR is a novel inhibitor of synaptic transmission that acts primarily on the presynaptic side with functional consequences for excitatory synaptic transmission and vesicle cycling in postnatal CAR knockout mice.
For behavioral analysis and field recordings with matching gene expression, we used adult mice. Analysis of function mEPSC , morphology, and gene expression in postnatal and adult animals is described below and in the online supplement. The Affymetrix Exon Mouse Chips 1. Additional details and information on the qRT-PCR probes and antibodies is available in the online supplement.
The BioID assay was performed based on the description of Roux et al. Details on the DNA constructs and the assay is available online. Biotinlylated proteins were enriched using Streptavidin-Dynabeads and identified by Massspectrometry. The automated Yeast-two-hybrid screen was performed as described previously We used the decay function of one trace to compensate for the endocytic component of the same trace Values were plotted as cumulative release over time. To record extracellular neuronal field responses, hippocampal slices of 3-month-old animals were prepared as previously described Field and mEPSC recodings are described in detail online.
Barnes Maze analysis was performed as described in the online supplement with mice trained for four days to find the hidden box positioned under the target hole. The movement of mice during the conditioning, context and cue analysis was observed via the camera of the context-fear-conditioning setup and the percentage of freezing was calculated by the Med-Software Med Associates. The Open Field test was carried out in the native cage environment. Statistical analysis was performed using unpaired-t test by GraphPad.
Additional details are available online. For statistical analysis, we used GraphPad Prism 5. Statistical significance between groups was determined using the Mann Whitney U test for electrophysiology data.
Expression values were compared using an unpaired two-tailed t test to assess differences between two groups. All data generated or analyzed during this study are included in this published article and the Supplementary Information files. Yamagata, M. Synaptic adhesion molecules. Cell Biol. Fogel, A. Lateral assembly of the immunoglobulin protein SynCAM 1 controls its adhesive function and instructs synapse formation. EMBO J. Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina. Nature , — Dalva, M.
Cell adhesion molecules: signalling functions at the synapse. Bukalo, O.
Synaptic cell adhesion molecules. Cell-cell communication mediated by the CAR subgroup of immunoglobulin cell adhesion molecules in health and disease. Chamma, I. Dynamics, nanoscale organization, and function of synaptic adhesion molecules. Robbins, E.
SynCAM 1 adhesion dynamically regulates synapse number and impacts plasticity and learning. Neuron 68 , — The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles. Neuron 52 , — Polo-Parada, L. Neuron 46 , — Bergelson, J. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science , — Carson, S.
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Purification of the putative coxsackievirus B receptor from HeLa cells. Fechner, H.
Induction of coxsackievirus-adenovirus-receptor expression during myocardial tissue formation and remodeling: identification of a cell-to-cell contact-dependent regulatory mechanism. Circulation , — Honda, T. The coxsackievirus-adenovirus receptor protein as a cell adhesion molecule in the developing mouse brain. Brain ResMolBrain Res 77 , 19—28 Asher, D. Coxsackievirus and adenovirus receptor is essential for cardiomyocyte development. Genesis 42 , 77—85 Dorner, A. Coxsackievirus-adenovirus receptor CAR is essential for early embryonic cardiac development.
JCell Sci , — Lim, B. Coxsackievirus and adenovirus receptor CAR mediates atrioventricular-node function and connexin 45 localization in the murine heart. Lisewski, U. The tight junction protein CAR regulates cardiac conduction and cell-cell communication.