(glial cell membrane)
- Novel insights into role of miR-320a-VDAC1 axis in astrocyte-mediated neuronal damage in neuroAIDS. [Journal Article]
- GLIAGlia 2016 Oct 20
- Astroglia are indispensable component of the tripartite synapse ensheathing innumerous soma and synapses. Its proximity to neurons aids the regulation of neuronal functions, health and survival throu...
Astroglia are indispensable component of the tripartite synapse ensheathing innumerous soma and synapses. Its proximity to neurons aids the regulation of neuronal functions, health and survival through dynamic neuroglia crosstalk. Susceptibility of astrocyte to HIV-1 infection and subsequent latency culminates in compromised neuronal health. The viral protein HIV-1 transactivator of transcription (Tat) is neurotoxic. HIV-1 Tat is detected in brain of AIDS patients even in cases where viral load is non-detectable due to successful HAART therapy. Recently, we demonstrated that HIV-1 Tat triggers excess ATP release from astrocytes that causes neuronal death by activating purinergic receptor system. Using well-characterized model system of human primary astrocytes and neurons, we probed into the molecular mechanism for enhanced ATP release in HIV-1 Tat affected astrocytes. HIV-1 Tat modulated the miRNA machinery in astrocytes and perturbed the levels of voltage dependent anion channel 1 (VDAC1), a channel present in the outer mitochondrial membrane and plasma membrane that regulates extracellular ATP release. Our studies with autopsy tissue sections also showed concordantly dysregulated VDAC1 and miR-320a levels in HIV-1 patients suffering from mild cognitive impairment (MCI). We report a novel molecular cascade of miRNA-mediated ATP release through regulation of VDAC1. Downregulation of VDAC1 either with miR-320a mimic or VDAC1 siRNA in HIV-1 Tat-affected astroglia could rescue the neurons from glia-mediated indirect death. Our findings reveal a novel upstream therapeutic target that could be employed to thwart the astroglia-mediated neurotoxicity in HIV-1 neuropathogenesis. GLIA 2016.
- Quantification of the functional expression of the Ca(2+) -activated K(+) channel KCa 3.1 on microglia from adult human neocortical tissue. [Journal Article]
- GLIAGlia 2016 Jul 29
- The KCa 3.1 channel (KCNN4) is an important modulator of microglia responses in rodents, but no information exists on functional expression on microglia from human adults. We isolated and cultured mi...
The KCa 3.1 channel (KCNN4) is an important modulator of microglia responses in rodents, but no information exists on functional expression on microglia from human adults. We isolated and cultured microglia (max 1% astrocytes, no neurons or oligodendrocytes) from neocortex surgically removed from epilepsy patients and employed electrophysiological whole-cell measurements and selective pharmacological tools to elucidate functional expression of KCa 3.1. The channel expression was demonstrated as a significant increase in the voltage-independent current by NS309, a KCa 3.1/KCa 2 activator, followed by full inhibition upon co-application with NS6180, a highly selective KCa 3.1 inhibitor. A major fraction (79%) of unstimulated human microglia expressed KCa 3.1, and the difference in current between full activation and inhibition (ΔKCa 3.1) was estimated at 292 ± 48 pA at -40 mV (n = 75), which equals at least 585 channels per cell. Serial KCa 3.1 activation/inhibition significantly hyperpolarized/depolarized the membrane potential. The isolated human microglia were potently activated by lipopolysaccharide (LPS) shown as a prominent increase in TNF-α production. However, incubation with LPS neither changed the KCa 3.1 current nor the fraction of KCa 3.1 expressing cells. In contrast, the anti-inflammatory cytokine IL-4 slightly increased the KCa 3.1 current per cell, but as the membrane area also increased, there was no significant change in channel density. A large fraction of the microglia also expressed a voltage-dependent current sensitive to the KCa 1.1 modulators NS1619 and Paxilline and an inward-rectifying current with the characteristics of a Kir channel. The high functional expression of KCa 3.1 in microglia from epilepsy patients accentuates the need for further investigations of its role in neuropathological processes. GLIA 2016.
- Role of Purines in Müller Glia. [Journal Article]
- JOJ Ocul Pharmacol Ther 2016; 32(8):518-533
- Müller glia, the principal macroglia of the retina, express diverse subtypes of adenosine and metabotropic purinergic (P2Y) receptors. Müller cells of several species, including man, also express ion...
Müller glia, the principal macroglia of the retina, express diverse subtypes of adenosine and metabotropic purinergic (P2Y) receptors. Müller cells of several species, including man, also express ionotropic P2X7 receptors. ATP is liberated from Müller cells after activation of metabotropic glutamate receptors and during osmotic and mechanical induction of membrane stretch; adenosine is released through equilibrative nucleoside transporters. Müller cell-derived purines modulate the neuronal activity and have autocrine effects, for example, induction of glial calcium waves and regulation of the cellular volume. Glial calcium waves induced by neuron-derived ATP mediate functional hyperemia in the retina. Purinergic signaling contributes to the induction of Müller cell gliosis, for example, of cellular proliferation and downregulation of potassium channels, which are important for the homeostatic functions of Müller cells. Purinergic glial calcium waves may also promote the long-range propagation of gliosis and neuronal degeneration across the retinal tissue. The osmotic ATP release is inhibited under pathological conditions. Inhibition of the ATP release may result in osmotic Müller cell swelling and dysregulation of the water transport through the cells; both may contribute to the development of retinal edema. Suppression of the osmotic ATP release and upregulation of the ecto-apyrase (NTPDase1), which facilitate the extracellular degradation of ATP and the formation of adenosine, may protect neurons and photoreceptors from death due to overactivation of P2X receptors. Pharmacological inhibition of P2X7 receptors and stimulation of adenosine receptors may represent clinical approaches to prevent retinal cell death and dysregulated cell proliferation, and to treat retinal edema.
- Removal of aquaporin-4 from glial and ependymal membranes causes brain water accumulation. [Journal Article]
- MCMol Cell Neurosci 2016 Oct 14
- There is a constitutive production of water in brain. The efflux routes of this excess water remain to be identified. We used basal brain water content as a proxy for the capacity of water exit route...
There is a constitutive production of water in brain. The efflux routes of this excess water remain to be identified. We used basal brain water content as a proxy for the capacity of water exit routes. Basal brain water content was increased in mice with a complete loss of aquaporin-4 (AQP4) water channels (global Aqp4(-/-) mice), but not in mice with a selective removal of perivascular AQP4 or in a novel mouse line with a selective deletion of ependymal AQP4 (Foxj1-Cre-Aqp4(flox/flox) mice). Unique for the global Aqp4(-/-) mice is the loss of the AQP4 pool subjacent to the pial membrane. Our data suggest that water accumulates in brain when subpial AQP4 is missing, pointing to a critical role of this pool of water channels in brain water exit.
- Importance of astrocytes for potassium ion (K(+)) homeostasis in brain and glial effects of K(+) and its transporters on learning. [Review]
- NBNeurosci Biobehav Rev 2016 Sep 28; 71:484-505
- Initial clearance of extracellular K(+) ([K(+)]o) following neuronal excitation occurs by astrocytic uptake, because elevated [K(+)]o activates astrocytic but not neuronal Na(+),K(+)-ATPases. Subsequ...
Initial clearance of extracellular K(+) ([K(+)]o) following neuronal excitation occurs by astrocytic uptake, because elevated [K(+)]o activates astrocytic but not neuronal Na(+),K(+)-ATPases. Subsequently, astrocytic K(+) is re-released via Kir4.1 channels after distribution in the astrocytic functional syncytium via gap junctions. The dispersal ensures widespread release, preventing renewed [K(+)]o increase and allowing neuronal Na(+),K(+)-ATPase-mediated re-uptake. Na(+),K(+)-ATPase operation creates extracellular hypertonicity and cell shrinkage which is reversed by the astrocytic cotransporter NKCC1. Inhibition of Kir channels by activation of specific PKC isotypes may decrease syncytial distribution and enable physiologically occurring [K(+)]o increases to open L-channels for Ca(2+), activating [K(+)]o-stimulated gliotransmitter release and regulating gap junctions. Learning is impaired when [K(+)]o is decreased to levels mainly affecting astrocytic membrane potential or Na(+),K(+)-ATPase or by abnormalities in its α2 subunit. It is enhanced by NKCC1-mediated ion and water uptake during the undershoot, reversing neuronal inactivity, but impaired in migraine with aura in which [K(+)]o is highly increased. Vasopressin augments NKCC1 effects and facilitates learning. Enhanced myelination, facilitated by astrocytic-oligodendrocytic gap junctions also promotes learning.
- Zinc Oxide Nanoparticle Induces Microglial Death by NADPH-Oxidase-Independent Reactive Oxygen Species as well as Energy Depletion. [Journal Article]
- MNMol Neurobiol 2016 Oct 6
- Zinc oxide nanoparticle (ZnO-NP) is one of the most widely used engineered nanoparticles. Upon exposure, nanoparticle can eventually reach the brain through various routes, interact with different br...
Zinc oxide nanoparticle (ZnO-NP) is one of the most widely used engineered nanoparticles. Upon exposure, nanoparticle can eventually reach the brain through various routes, interact with different brain cells, and alter their activity. Microglia is the fastest glial cell to respond to any toxic insult. Nanoparticle exposure can activate microglia and induce neuroinflammation. Simultaneous to activation, microglial death can exacerbate the scenario. Therefore, we focused on studying the effect of ZnO-NP on microglia and finding out the pathway involved in the microglial death. The present study showed that the 24 h inhibitory concentration 50 (IC50) of ZnO-NP for microglia is 6.6 μg/ml. Early events following ZnO-NP exposure involved increase in intracellular calcium level as well as reactive oxygen species (ROS). Neither of NADPH oxidase inhibitors, apocynin, (APO) and diphenyleneiodonium chloride (DPIC) were able to reduce the ROS level and rescue microglia from ZnO-NP toxicity. In contrary, N-acetyl cysteine (NAC) showed opposite effect. Exogenous supplementation of superoxide dismutase (SOD) reduced ROS significantly even beyond control level but partially rescued microglial viability. Interestingly, pyruvate supplementation rescued microglia near to control level. Following 10 h of ZnO-NP exposure, intracellular ATP level was measured to be almost 50 % to the control. ZnO-NP-induced ROS as well as ATP depletion both disturbed mitochondrial membrane potential and subsequently triggered the apoptotic pathway. The level of apoptosis-inducing proteins was measured by western blot analysis and found to be upregulated. Taken together, we have deciphered that ZnO-NP induced microglial apoptosis by NADPH oxidase-independent ROS as well as ATP depletion.
- Adenosine A2A receptor and ecto-5'-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE). [Journal Article]
- PSPurinergic Signal 2016 Sep 20
- Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A2A receptor emerges a...
Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A1 receptors. Gain of function of the excitatory A2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A2A receptor and of the adenosine-generating enzyme, ecto-5'-nucleotidase/CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No co-localization was observed between the A2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A2A receptor and ecto-5'-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5'-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients.
- Autoantibody-Associated Central Nervous System Neurologic Disorders. [Journal Article]
- SNSemin Neurol 2016; 36(4):382-96
- Autoimmune neurology is a rapidly evolving new subspecialty driven by the discovery of novel neural- (neuronal- or glial-) specific autoantibodies and their target antigens. The neurologic manifestat...
Autoimmune neurology is a rapidly evolving new subspecialty driven by the discovery of novel neural- (neuronal- or glial-) specific autoantibodies and their target antigens. The neurologic manifestations affecting the central nervous system include encephalitis, dementia, epilepsy, and movement and sleep disorders. Laboratory testing is now available for most of these neural-specific autoantibodies, which serve as diagnostic markers, in some instances directing the physician toward specific cancer types (e.g., N-methyl-D-aspartic acid receptor antibodies for teratoma, collapsin response mediator protein 5 for small-cell lung cancer) and assisting in therapeutic decision making. Antibodies targeting intracellular proteins serve as markers of cytotoxic effector T-cell-mediated injury, which is generally poorly responsive to immunotherapy. By contrast, antibodies targeting extracellular plasma membrane proteins may act as pathogenic effectors and often infer good responses to immunotherapy. Diagnosing these conditions and implementing treatment as early into the clinical course as possible ensures the best possible clinical outcomes. An adequate immunotherapy trial to assess maximum reversibility of symptoms, as assessed through objective functional measures, is crucial and can help to determine whether maintenance therapy is needed.
- Fluid levity of the cell: Role of membrane lipid architecture in genetic sphingolipidoses. [Journal Article]
- JNJ Neurosci Res 2016; 94(11):1019-24
- Sphingolipidoses arise from inherited loss of function of key enzymes regulating the sphingolipid (SL) metabolism and the accumulation of large quantities of these lipids in affected cells. Most freq...
Sphingolipidoses arise from inherited loss of function of key enzymes regulating the sphingolipid (SL) metabolism and the accumulation of large quantities of these lipids in affected cells. Most frequently, toxicity is manifested in the nervous system, where survival and function of neurons and glial cells are most affected. Although detailed information is available on neuroglial alterations during terminal stages of the disease, the initial pathogenic mechanisms triggering neuropathology are largely unclear. Because they are key components of biological membranes, changes in the local concentration of SLs are likely to impact the organization of membrane domains and functions. This Commentary proposes that SL toxicity involves initial defects in the integrity of lipid domains, membrane fluidity, and membrane bending, leading to membrane deformation and deregulation of cell signaling and function. Understanding how SLs alter membrane architecture may provide breakthroughs for more efficient treatment of sphingolipidoses. © 2016 Wiley Periodicals, Inc.
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- Astroglial Vesicular Trafficking in Neurodegenerative Diseases. [Journal Article]
- NRNeurochem Res 2016 Sep 14
- The neocortex represents one of the largest estates of the human brain. This structure comprises ~30-40 billions of neurones and even more of non-neuronal cells. Astrocytes, highly heterogeneous homo...
The neocortex represents one of the largest estates of the human brain. This structure comprises ~30-40 billions of neurones and even more of non-neuronal cells. Astrocytes, highly heterogeneous homoeostatic glial cells, are fundamental for housekeeping of the brain and contribute to information processing in neuronal networks. Gray matter astrocytes tightly enwrap synapses, contact blood vessels and, naturally, are also in contact with the extracellular space, where convection of fluid takes place. Thus astrocytes receive signals from several distinct extracellular domains and can get excited by numerous mechanisms, which regulate cytosolic concentration of second messengers, such as Ca(2+) and cAMP. Excited astrocytes often secrete diverse substances (generally referred to as gliosignalling molecules) that include classical neurotransmitters such as glutamate and ATP or neuromodulators such as D-serine or neuropeptides. Astrocytic secretion occurs through several mechanisms: by diffusion through membrane channels, by translocation via plasmalemmal transporters or by vesicular exocytosis. Vesicular release of gliosignalling molecules appears fundamentally similar to that operating in neurones, since it depends on the SNARE proteins-dependent merger of the vesicle membrane with the plasmalemma. However, the coupling between the stimulus and astroglial vesicular secretion is at least one order of magnitude slower than that in neurones. Here we review mechanisms of astrocytic excitability and the molecular, anatomical and physiological properties of vesicular apparatus mediating the release of gliosignalling molecules in health and in the neurodegenerative pathology.