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Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis.

Del Rio R, Quintanilla RA, Orellana JA, Retamal MA - Front Physiol (2015)

Bottom Line: One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system.Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells.In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigación Biomédica, Universidad Autónoma de Chile Santiago, Chile ; Dirección de Investigación, Universidad Científica del Sur Lima, Perú

ABSTRACT
Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of glia-to-neuron communication. Glial cells release gliotransmitters (e.g., glutamate, D-serine, and ATP) through Ca2+- and SNARE-dependent exocytosis (1) in addition to the release that occurs through alternative non-exocytotic pathways (see below). Depolarization, reductions in extracellular divalent cation concentrations, increases in intracellular Ca2+ and posttranslational modifications might result in the opening of connexin and pannexin hemichannels (HCs) and thus allow the release of gliotransmitters (2). Long-lasting activation of P2X7 by ATP might lead to the appearance of large currents and the rapid exchange of large molecules, including the release of gliotransmitters (3). One theory states that P2X7 receptor conductance dilates over the time and thereby allows the passage of large molecules; however, another hypothesis states that ATP activate a second non-selective permeabilization pathway (Baroja-Mazo et al., 2013). Recently, it was shown that Panx1 hemichannels might mediate this permeability for large molecules in astrocytes (4) (Iglesias et al., 2009). Additionally, gliotransmitter release may occur through volume-regulated anion channels (VRAC) (5) and different carriers and/or co-transporters acting normally or in reverse (6) (e.g., excitatory amino-acid transporters, the cystine-glutamate antiporter, and the D-serine/chloride co-transporter). Within the last decade, a growing body of evidence has indicated that glial cells can also communicate with neurons via the release of vesicles (e.g., exosomes, microparticles, and apoptotic bodies), containing different cellular messengers (e.g., mRNA, viruses, and organelles) (7). Adjacent glial cells and neurons can communicate directly through F-actin-based transient tubular connections known as tunneling nanotubes (8), via cell-to-cell contacts between membrane-bound ligand molecules and their receptors (9) or aggregates of intercellular channels known as gap junctions, which allow the exchange of small molecules (10).
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Figure 1: Mechanisms of glia-to-neuron communication. Glial cells release gliotransmitters (e.g., glutamate, D-serine, and ATP) through Ca2+- and SNARE-dependent exocytosis (1) in addition to the release that occurs through alternative non-exocytotic pathways (see below). Depolarization, reductions in extracellular divalent cation concentrations, increases in intracellular Ca2+ and posttranslational modifications might result in the opening of connexin and pannexin hemichannels (HCs) and thus allow the release of gliotransmitters (2). Long-lasting activation of P2X7 by ATP might lead to the appearance of large currents and the rapid exchange of large molecules, including the release of gliotransmitters (3). One theory states that P2X7 receptor conductance dilates over the time and thereby allows the passage of large molecules; however, another hypothesis states that ATP activate a second non-selective permeabilization pathway (Baroja-Mazo et al., 2013). Recently, it was shown that Panx1 hemichannels might mediate this permeability for large molecules in astrocytes (4) (Iglesias et al., 2009). Additionally, gliotransmitter release may occur through volume-regulated anion channels (VRAC) (5) and different carriers and/or co-transporters acting normally or in reverse (6) (e.g., excitatory amino-acid transporters, the cystine-glutamate antiporter, and the D-serine/chloride co-transporter). Within the last decade, a growing body of evidence has indicated that glial cells can also communicate with neurons via the release of vesicles (e.g., exosomes, microparticles, and apoptotic bodies), containing different cellular messengers (e.g., mRNA, viruses, and organelles) (7). Adjacent glial cells and neurons can communicate directly through F-actin-based transient tubular connections known as tunneling nanotubes (8), via cell-to-cell contacts between membrane-bound ligand molecules and their receptors (9) or aggregates of intercellular channels known as gap junctions, which allow the exchange of small molecules (10).

Mentions: Gliotransmission is part of the basis of “neuron-glia crosstalk” and multiple mechanisms have been described to mediate gliotransmitter release, including the Ca2+-dependent exocytosis (Bezzi et al., 2004; Zhang et al., 2004; Imura et al., 2013), carrier membrane transport (Rossi et al., 2000) and opening of a wide-range of channels encompassing P2X7 channels (Duan et al., 2003; Suadicani et al., 2006; Hamilton et al., 2008), volume-regulated anion channels (Kimelberg et al., 1990; Takano et al., 2005; Rudkouskaya et al., 2008; Lee et al., 2010) and connexin hemichannels (Stout et al., 2002; Ye et al., 2003) (Figure 1). Though most studies regarding neuron-glia crosstalk have been focused in gliotransmitter release, in the last decade it has become evident that brain cells can communicate via alternative mechanisms. Among them are those relying on heterotypic glia-to-neuron contacts mediated by homophylic and heterophylic adhesion molecule interactions (Avalos et al., 2009; Sandau et al., 2011) (Figure 1). Importantly, vesicles containing molecules/organelles (e.g., exosomes, microparticles, and apoptotic bodies) have resulted in an new unexpected mechanism of brain cell communication, allowing the exchange of gliotransmitters, organelles, genetic information, proteins, and infectious agents between glial cells and neurons (Frühbeis et al., 2013). Direct astrocyte-to-neuron communication not only occur through GJCs (Fróes et al., 1999; Rozental et al., 2001; Dobrenis et al., 2005), but also via intercellular bridges or long cellular extensions called intercellular nanotubes (Wang et al., 2012) (Figure 1). In the next section, we focused in a specific route of gliotransmitter communication mediated by single membrane channels called “hemichannels.”


Neuron-Glia Crosstalk in the Autonomic Nervous System and Its Possible Role in the Progression of Metabolic Syndrome: A New Hypothesis.

Del Rio R, Quintanilla RA, Orellana JA, Retamal MA - Front Physiol (2015)

Mechanisms of glia-to-neuron communication. Glial cells release gliotransmitters (e.g., glutamate, D-serine, and ATP) through Ca2+- and SNARE-dependent exocytosis (1) in addition to the release that occurs through alternative non-exocytotic pathways (see below). Depolarization, reductions in extracellular divalent cation concentrations, increases in intracellular Ca2+ and posttranslational modifications might result in the opening of connexin and pannexin hemichannels (HCs) and thus allow the release of gliotransmitters (2). Long-lasting activation of P2X7 by ATP might lead to the appearance of large currents and the rapid exchange of large molecules, including the release of gliotransmitters (3). One theory states that P2X7 receptor conductance dilates over the time and thereby allows the passage of large molecules; however, another hypothesis states that ATP activate a second non-selective permeabilization pathway (Baroja-Mazo et al., 2013). Recently, it was shown that Panx1 hemichannels might mediate this permeability for large molecules in astrocytes (4) (Iglesias et al., 2009). Additionally, gliotransmitter release may occur through volume-regulated anion channels (VRAC) (5) and different carriers and/or co-transporters acting normally or in reverse (6) (e.g., excitatory amino-acid transporters, the cystine-glutamate antiporter, and the D-serine/chloride co-transporter). Within the last decade, a growing body of evidence has indicated that glial cells can also communicate with neurons via the release of vesicles (e.g., exosomes, microparticles, and apoptotic bodies), containing different cellular messengers (e.g., mRNA, viruses, and organelles) (7). Adjacent glial cells and neurons can communicate directly through F-actin-based transient tubular connections known as tunneling nanotubes (8), via cell-to-cell contacts between membrane-bound ligand molecules and their receptors (9) or aggregates of intercellular channels known as gap junctions, which allow the exchange of small molecules (10).
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Figure 1: Mechanisms of glia-to-neuron communication. Glial cells release gliotransmitters (e.g., glutamate, D-serine, and ATP) through Ca2+- and SNARE-dependent exocytosis (1) in addition to the release that occurs through alternative non-exocytotic pathways (see below). Depolarization, reductions in extracellular divalent cation concentrations, increases in intracellular Ca2+ and posttranslational modifications might result in the opening of connexin and pannexin hemichannels (HCs) and thus allow the release of gliotransmitters (2). Long-lasting activation of P2X7 by ATP might lead to the appearance of large currents and the rapid exchange of large molecules, including the release of gliotransmitters (3). One theory states that P2X7 receptor conductance dilates over the time and thereby allows the passage of large molecules; however, another hypothesis states that ATP activate a second non-selective permeabilization pathway (Baroja-Mazo et al., 2013). Recently, it was shown that Panx1 hemichannels might mediate this permeability for large molecules in astrocytes (4) (Iglesias et al., 2009). Additionally, gliotransmitter release may occur through volume-regulated anion channels (VRAC) (5) and different carriers and/or co-transporters acting normally or in reverse (6) (e.g., excitatory amino-acid transporters, the cystine-glutamate antiporter, and the D-serine/chloride co-transporter). Within the last decade, a growing body of evidence has indicated that glial cells can also communicate with neurons via the release of vesicles (e.g., exosomes, microparticles, and apoptotic bodies), containing different cellular messengers (e.g., mRNA, viruses, and organelles) (7). Adjacent glial cells and neurons can communicate directly through F-actin-based transient tubular connections known as tunneling nanotubes (8), via cell-to-cell contacts between membrane-bound ligand molecules and their receptors (9) or aggregates of intercellular channels known as gap junctions, which allow the exchange of small molecules (10).
Mentions: Gliotransmission is part of the basis of “neuron-glia crosstalk” and multiple mechanisms have been described to mediate gliotransmitter release, including the Ca2+-dependent exocytosis (Bezzi et al., 2004; Zhang et al., 2004; Imura et al., 2013), carrier membrane transport (Rossi et al., 2000) and opening of a wide-range of channels encompassing P2X7 channels (Duan et al., 2003; Suadicani et al., 2006; Hamilton et al., 2008), volume-regulated anion channels (Kimelberg et al., 1990; Takano et al., 2005; Rudkouskaya et al., 2008; Lee et al., 2010) and connexin hemichannels (Stout et al., 2002; Ye et al., 2003) (Figure 1). Though most studies regarding neuron-glia crosstalk have been focused in gliotransmitter release, in the last decade it has become evident that brain cells can communicate via alternative mechanisms. Among them are those relying on heterotypic glia-to-neuron contacts mediated by homophylic and heterophylic adhesion molecule interactions (Avalos et al., 2009; Sandau et al., 2011) (Figure 1). Importantly, vesicles containing molecules/organelles (e.g., exosomes, microparticles, and apoptotic bodies) have resulted in an new unexpected mechanism of brain cell communication, allowing the exchange of gliotransmitters, organelles, genetic information, proteins, and infectious agents between glial cells and neurons (Frühbeis et al., 2013). Direct astrocyte-to-neuron communication not only occur through GJCs (Fróes et al., 1999; Rozental et al., 2001; Dobrenis et al., 2005), but also via intercellular bridges or long cellular extensions called intercellular nanotubes (Wang et al., 2012) (Figure 1). In the next section, we focused in a specific route of gliotransmitter communication mediated by single membrane channels called “hemichannels.”

Bottom Line: One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system.Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells.In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigación Biomédica, Universidad Autónoma de Chile Santiago, Chile ; Dirección de Investigación, Universidad Científica del Sur Lima, Perú

ABSTRACT
Metabolic syndrome (MS) is characterized by the following physiological alterations: increase in abdominal fat, insulin resistance, high concentration of triglycerides, low levels of HDL, high blood pressure, and a generalized inflammatory state. One of the pathophysiological hallmarks of this syndrome is the presence of neurohumoral activation, which involve autonomic imbalance associated to hyperactivation of the sympathetic nervous system. Indeed, enhanced sympathetic drive has been linked to the development of endothelial dysfunction, hypertension, stroke, myocardial infarct, and obstructive sleep apnea. Glial cells, the most abundant cells in the central nervous system, control synaptic transmission, and regulate neuronal function by releasing bioactive molecules called gliotransmitters. Recently, a new family of plasma membrane channels called hemichannels has been described to allow the release of gliotransmitters and modulate neuronal firing rate. Moreover, a growing amount of evidence indicates that uncontrolled hemichannel opening could impair glial cell functions, affecting synaptic transmission and neuronal survival. Given that glial cell functions are disturbed in various metabolic diseases, we hypothesize that progression of MS may relies on hemichannel-dependent impairment of glial-to-neuron communication by a mechanism related to dysfunction of inflammatory response and mitochondrial metabolism of glial cells. In this manuscript, we discuss how glial cells may contribute to the enhanced sympathetic drive observed in MS, and shed light about the possible role of hemichannels in this process.

No MeSH data available.


Related in: MedlinePlus