Functions of connexins and large pore channels on microglial cells: The gates to environment

Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, D-44780 Bochum, Germany.
Brain research (Impact Factor: 2.84). 07/2012; 1487. DOI: 10.1016/j.brainres.2012.07.020
Source: PubMed


Microglial cells are not only sensitive indicators for pathology of the central nervous system (CNS), they are a key factor for neurotoxicity and degeneration in many diseases. Neuronal damage leads to reactive gliosis and to activation of microglia including cytoarchitectonic changes accompanied by alterations in surface receptor and channel expression. In this context, the release of neuroactive soluble factors like pro-inflammatory cytokines can result in increased cellular motility and a higher grade of phagocytotic activity. Ligands including glutamate, tumor necrosis factor alpha (TNF-α), cytokines, superoxide radicals and neurotrophins released by microglia have in turn effects on neuronal function and cell death. The current review focuses on large pore and hemichannel function in microglial cells under different conditions of activation and elucidates the role of these channels in cytokine release, as well as putative targets for clinical intervention in case of inflammatory processes. This article is part of a Special Issue entitled Electrical Synapses.

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    • "The repertoire of Cx protein expression is distinct among various CNS cell types; however, the functional impact of these differences remains to be fully defined. For example, astrocytes primarily express Cx43 and Cx30, as well as, Cx26, Cx40, Cx45 and Cx46; microglia utilize Cx43, Cx36, and Cx32; and neurons express Cx36, Cx26, Cx45, and Cx57 (Rouach et al., 2002; Mika and Prochnow, 2012). Studies have shown that a selective pattern of Cx HC expression may orchestrate extracellular signaling networks between various glial cell types and/or neurons in a homotypic or heterotypic fashion (Giaume et al., 2013; May et al., 2013). "
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    ABSTRACT: Although originally considered a structural component of gap junctions, connexin hemichannels (HCs) are now recognized as functional entities capable of influencing metabolic gradients within the CNS, allowing direct communication between the intra- and extracellular milieus. Besides connexins, HCs can also be formed by pannexins, which are not capable of gap junction assembly. Both positive and negative effects have been attributed to HC activity in the context of neurodegenerative diseases. For example, HCs can exert neuroprotective effects by promoting the uptake of neurotoxic molecules, whereas chronic HC opening can disrupt molecular gradients leading to cellular dysfunction and death. The latter scenario has been suggested for multiple neurodegenerative disorders, including Alzheimer's disease (AD) and more recently, lysosomal storage disorders, which are the focus of this perspective. Currently available evidence suggests a complex role for HCs in neurodegenerative disorders, which sets the stage for future studies to determine whether targeting HC action may improve disease outcomes.
    Full-text · Article · Aug 2014 · Frontiers in Cellular Neuroscience
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    • "As it is well known, hemichannels participate in diverse functions of CNS (reviewed by Menichella et al., 2003; Kielian, 2008; Kleopa et al., 2010; Abrams and Scherer, 2012; Mika and Prochnow, 2012; Belousov and Fontes, 2013). Since Cxs proteins are expressed in several CNS regions involved in central chemoreception, it is possible that hemichannels may play a role in pH/CO2 sensing. "
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    ABSTRACT: Connexins (Cxs) and Pannexins (Panx) form hemichannels at the plasma membrane of animals. Despite their low open probability under physiological conditions, these hemichannels release signaling molecules (i.e. ATP, Glutamate, PGE2) to the extracellular space, thus subserving in several important physiological processes. Oxygen and CO2 sensing are fundamental to the normal functioning of vertebrate organisms. Fluctuations in blood PO2, PCO2 and pH are sensed at the carotid bifurcations of adult mammals by glomus cells of the carotid bodies. Likewise, changes in pH and/or PCO2 of cerebrospinal fluid are sensed by central chemoreceptors, a group of specialized neurones distributed in the ventrolateral medulla, raphe nuclei, and some other brainstem areas. After many years of research, the molecular mechanisms involved in chemosensing process are not completely understood. This manuscript will review data regarding relationships between chemosensitive cells and the expression of channels formed by Cxs and Panx, with special emphasis in hemichannels.
    Full-text · Article · Mar 2014 · Frontiers in Cellular Neuroscience
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    • "In mice and humans, Connexins are encoded by a family with 20 and 21 genes, respectively (Berthoud and Beyer, 2009). In the CNS of rodents, the majority of Connexin isoforms (n = 11) are expressed by glial cells (Prochnow and Dermietzel, 2008; Giaume and Theis, 2010; Mika and Prochnow, 2012; Rash et al., 2012). Among others, Cx36 gives rise to the main neuronal gap junction channel forming protein (Belluardo et al., 2000; Venance et al., 2000; Rash et al., 2012; Belousov and Fontes, 2013). "
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    ABSTRACT: In case of traumatic brain injury (TBI), occurrence of central nervous tissue damage is frequently aligned with local modulations of neuronal and glial gap junction channel expression levels. The degree of gap junctional protein expression and intercellular coupling efficiency, as well as hemichannel function has substantially impact on the course of trauma recovery and outcome. During TBI, gap junctions are especially involved in the intercellular molecule trafficking on repair of blood vessels and the regulation of vasomotor tone. Furthermore, gliosis and astrocytic swelling due to mechanical strain injury point out the consequences of derailed gap junction communication. This review addresses the outstanding role of gap junction channels in TBI pathophysiology and links the current state of results to applied clinical procedures as well as perspectives in acute and long-term treatment options.
    Full-text · Article · Feb 2014 · Frontiers in Physiology
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