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: 2.46). 07/2012; DOI: 10.1016/j.brainres.2012.07.020
Source: PubMed

ABSTRACT 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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    ABSTRACT: For decades, studies have been focusing on the neuronal abnormalities that accompany neurodegenerative disorders. Yet, glial cells are emerging as important players in numerous neurological diseases. Because reactive astrocytes are associated with a variety of central nervous system (CNS) disorders, interest in the glial contribution to neuronal injury is exponentially increasing. Astrocytes, the main type of glia in the CNS, form extensive networks that physically and functionally connect neuronal synapses with cerebral blood vessels. Normal brain functioning strictly depends on highly specialized cellular cross-talk between these different partners to which Ca(2+), as a signaling ion, largely contributes. Altered intracellular Ca(2+) levels are associated with neurodegenerative processes/diseases and play a crucial role in the glial responses to injury. Most importantly, intracellular Ca(2+) increases in single astrocytes can be propagated toward neighboring cells as intercellular Ca(2+) waves, thereby recruiting a larger group of cells. The propagation of intercellular Ca(2+) waves largely depends on two, parallel, connexin (Cx) channel-based mechanisms: i) the diffusion of inositol 1,4,5-trisphosphate through gap junction channels that directly connect the cytoplasm of neighboring cells, and ii) the release of paracrine messengers such as glutamate and ATP through hemichannels ('half of a gap junction channel'). This review gives an overview of the current knowledge on Cx-mediated Ca(2+) communication among astrocytes as well as between astrocytes and other brain cell types in physiology and pathology, with a focus on the processes of neurodegeneration and reactive gliosis. Research on Cx-mediated astroglial Ca(2+) communication may ultimately shed light on the development of targeted therapies for neurodegenerative disorders in which astrocytes participate. This article is part of a Special Issue entitled: Calcium signaling in health and disease.
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