Functions of connexins and large pore channels on microglial cells: The gates to environment.
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.
- SourceAvailable from: Mauricio A Retamal[Show abstract] [Hide abstract]
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.Frontiers in Cellular Neuroscience 03/2014; · 4.47 Impact Factor
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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.Frontiers in Physiology 01/2014; 5:31.
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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.Biochimica et Biophysica Acta 04/2014; · 4.66 Impact Factor