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Full-Text Articles in Medicine and Health Sciences
Neural-Glial-Vascular Interactions In Human Outer Retina, Deepayan Kar
Neural-Glial-Vascular Interactions In Human Outer Retina, Deepayan Kar
All ETDs from UAB
The outer retinal metabolic ecosystem is a complex interplay among photoreceptors, RPE and blood supply from the retinal and choroidal microcirculation. Breakdown of any component of this ecosystem has detrimental effects and can lead to cellular dysfunction. For example, in age-related macular degeneration a major cause of vision loss in older adults, breakdown of this metabolic unit has severe structural and functional implications. Thus, every feature and component of this ecosystem seems to be optimized to protect non-replicating, terminally differentiated cells from being damaged. Remarkably, much of the cellular and subcellular organization of this system is available for observation in …
The Role Of Protein O-Glcnacylation In Regulating Mitochondrial Function, Jalessa Nicole Wright
The Role Of Protein O-Glcnacylation In Regulating Mitochondrial Function, Jalessa Nicole Wright
All ETDs from UAB
The attachment of O-linked-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins has emerged as an important regulatory mechanism in transcriptional regulation, protein activation as well as cell survival. Several studies have reported that elevated O-GlcNAc levels have adverse effects on mitochondrial function. These negative effects have been linked to O-GlcNAc modification of mitochondrial proteins that are integral across multiple metabolic cell processes i.e. VDAC, NDUFA9 and DRP-1. Mitochondrial complexes I, III and IV all contain subunit proteins that are O-GlcNAc modified and increased O-GlcNAcylation of these proteins is associated with deficits in oxidative phosphorylation in these models. Conversely, it has …
The Contribution Of Mitochondrial Genetic Background To Glucose Metabolism And Insulin Sensitivity In Vivo, Melissa June Sammy
The Contribution Of Mitochondrial Genetic Background To Glucose Metabolism And Insulin Sensitivity In Vivo, Melissa June Sammy
All ETDs from UAB
It has been observed that the risk of developing diabetes increases with age as well as among certain races, most notably African Americans and Hispanic Americans who are almost two times as likely to develop perturbed glucose metabolism compared to Caucasian Americans. Interestingly, there are distinct mitochondrial DNA polymorphisms that distinguish people of different races and thus may contribute to differential susceptibility to diseases of glucose metabolism. To test the hypothesis that the mitochondrial DNA (mtDNA) contributes to glucose metabolism and insulin sensitivity, two strains of mice were used with distinct mtDNA sequences namely, C57BL6/J and C3H/HeN as well as …
The Effect Of Mitochondrial-Derived Ros On Calcium Handling And Cardiac Function In Heart, Kah Yong Goh
The Effect Of Mitochondrial-Derived Ros On Calcium Handling And Cardiac Function In Heart, Kah Yong Goh
All ETDs from UAB
Mitochondria are abundantly present in metabolic active organs such as the heart. The presence of mitochondria are crucial to provide energy in the form of ATP, regulate calcium handling, facilitate cell fate, and are involved in metabolic modulation. In the process of generating ATP through oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS) as a side product. In the heart, mitochondria is a major source of ROS. Under normal conditions, ROS are kept at a physiologically relevant and healthy level. Unfortunately, excessive ROS levels during pathological states, such as pressure overload heart failure, appears as a threat to the whole …
Mitochondria-To-Nucleus Retrograde Signaling And Its Role In Cancer, Trevor Carden
Mitochondria-To-Nucleus Retrograde Signaling And Its Role In Cancer, Trevor Carden
All ETDs from UAB
Mitochondrial dysfunction is considered a hallmark of cancer. Mitochondria are essential, cellular organelles that participate in processes including energy production, calcium homeostasis and steroid metabolism. Mitochondria have been more recently appreciated for their role in cellular signaling, bringing about a greater understanding of their role in many diseases including cancer. Retrograde signaling is a mechanism by which the nucleus responds to mitochondrial dysfunction by modulating its own transcriptional programs to maintain metabolic and cellular processes. Many genes have already been identified as participants in or mediators of this signaling mechanism; these include cell signaling, metabolic and structural genes as well …
Acute And Chronic Regulation Of Skeletal Muscle Mitochondrial Function, Jonathan Lund Warren
Acute And Chronic Regulation Of Skeletal Muscle Mitochondrial Function, Jonathan Lund Warren
All ETDs from UAB
Obesity and type 2 diabetes (T2D) represent a growing global burden on healthcare and financial resources. One hypothesis for the onset and exacerbation of these diseases is related to the role of mitochondria as the end users of products of the metabolism of the nutrients we consume and in mediating the oxidative state of the body through the production of reactive oxygen species (ROS). In order to meet the demands of a metabolic challenge and prevent excessive ROS production, there appear to be adaptations to mitochondrial physiology and morphology that can occur and we hypothesize that the ability of the …
Activation Of Ampk To Diminish Sepsis-Induced Lung Injury, Nathaniel Bone
Activation Of Ampk To Diminish Sepsis-Induced Lung Injury, Nathaniel Bone
All ETDs from UAB
Sepsis is the most frequent cause of death of hospitalized patients in modern ICUs. Severe infection, trauma, hemorrhage, burns, and surgery are significant causes of multi-organ injury and immune dysfunction that in turn primes for a high risk of secondary lung infections. In addition to detrimental inflammation, sepsis is linked to loss of metabolic plasticity due to mitochondrial dysfunction in immune cells and lung tissue. In particular, mitochondrial failure in lungs of critically ill septic patients is correlated with high mortality rates. We proposed that AMP-activated protein kinase (AMPK) activation, a major bioenergetic sensor and metabolic regulator, is a plausible …
The Impact Of Mitochondrial Genetic Background On Development Of Complex Multifactorial Diseases, Alexander Wendell Bray
The Impact Of Mitochondrial Genetic Background On Development Of Complex Multifactorial Diseases, Alexander Wendell Bray
All ETDs from UAB
Complex multifactorial diseases such as cardiovascular disease (CVD) and cancer are a pervasive and inescapable component of modern society. However, the genetic elements that modulate individual susceptibility to these diseases remain poorly defined. Excessive mitochondrial oxidant production has been implicated in the initiation and progression of both CVD and cancer. Moreover, polymorphisms inherited on the mitochondria genome appear to influence mammalian mitochondrial function and oxidant generation. In the present study, mitochondrial-nuclear-eXchange (MNX) mice were used to directly assess the contribution of mitochondrial DNA (mtDNA) polymorphisms to atherosclerosis in the apoE deficient (apoE-/-) mouse model of hypercholesterolemia induced atherogenesis. ApoE-/- mice …
Autophagy In Mitochondrial Quality Control And Proteotoxicity In Neurons, Matthew Redmann
Autophagy In Mitochondrial Quality Control And Proteotoxicity In Neurons, Matthew Redmann
All ETDs from UAB
Parkinson’s disease (PD) is the 2nd most common neurodegenerative disorder with aging as a significant risk factor. Sharing with aging brains, postmortem PD brains exhibit cellular deficits including autophagic dysfunction, mitochondrial dysfunction, and intracellular protein aggregates of alpha-synuclein. This dissertation will focus on the interplay between these key disease features. To that end, we coupled primary cortical neuronal cultures from either rats or mice with Seahorse extracellular flux, metabolomics and biochemical techniques. Autophagy is an important cell recycling program responsible for the clearance of damaged proteins and organelles. Bafilomycin A1 and chloroquine are compounds that inhibit autophagy by targeting the …
Histopathology And Image Validation Of Outer Retinal Tubulations In Age-Related Macular Degeneration, Katie M. Litts
Histopathology And Image Validation Of Outer Retinal Tubulations In Age-Related Macular Degeneration, Katie M. Litts
All ETDs from UAB
High-resolution imaging of the retina using spectral domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) is revealing new information about photoreceptor degeneration in age-related macular degeneration (AMD) and other diseases impacting rod and cone photoreceptors. By SD-OCT, the hyperreflective outer retinal bands are visible due to the precise vertical compartmentalization and horizontal alignment of outer retinal cells and tissues (Müller cells, photoreceptors, RPE, and Bruch’s membrane). Validating these bands with normal eyes is difficult because the outer retina is very delicate making accurate histology requiring attached retina and vertically aligned photoreceptors challenging. Conversely, the bands are …
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
All ETDs from UAB
Neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease are all characterized by metabolic dysfunction, increased oxidative damage to proteins and organelles, formation of proteinaceous inclusions, decreased autophagic and proteasomal function, and eventual neuronal and glial cell death. While our understanding of the mechanisms that underlie many of these pathologies is constantly growing, their exact cause, onset, interplay and progression still remain unclear. The gap between the description of disease pathologies and understanding the fundamental mechanisms of disease pathogenesis, progression and potential therapeutics to mitigate disease progression is still large. Based on the observation that altered glucose utilization, …
Bioenergetics As A Biomarker Of Health And Disease, Philip Kramer
Bioenergetics As A Biomarker Of Health And Disease, Philip Kramer
All ETDs from UAB
The increasing prevalence of metabolic syndrome, diabetes, atherosclerosis, and many other diseases only recently associated with aberrant metabolism, have led to a de-mand for clinical assays to determine a patient’s mitochondrial health. With the rapidly growing interest in personalized medicine, such an assay would ideally be able to capture the metabolic changes associated with oxidative stress, inflammation, and therapy of a patient in a swift and non-invasive manner. Short of tissue biopsies, this burgeoning field of Translational Bioenergetics has had minimal success in obtaining sufficient human cells and the means to assess them both accurately and swiftly. The purpose of …
Role Of Vapb/Als8 Signaling Through Lar Receptor, Jessica Lindsey Winek Schultz
Role Of Vapb/Als8 Signaling Through Lar Receptor, Jessica Lindsey Winek Schultz
All ETDs from UAB
In humans, a P56S point mutation in the VAPB/ALS8 MSP domain is associated with amyotrophic lateral sclerosis (ALS) and late-onset spinal muscular atrophy (SMA). The N-terminal MSP domain is cleaved from the C-terminus, and secreted through an unknown, nonconventional manner. The P56S mutation inhibits secretion of the MSP domain. We use Caenorhabditis elegans to study live secretion of VPR-1, as well as to understand vMSP receptor signaling in muscle and gonad. To study the secretion mechanism of VPR-1 we created a transgenic line of C. elegans with a fluorescently tagged VPR-1. Using this model, we were able to visualize live …
Mitochondrial Genetics Modify Body Composition, Metabolic Efficiency And Myocardial Metabolism, Kimberly Joanne Dunham
Mitochondrial Genetics Modify Body Composition, Metabolic Efficiency And Myocardial Metabolism, Kimberly Joanne Dunham
All ETDs from UAB
Obesity and cardiometabolic pathologies have reached epidemic levels worldwide over the last 30 years. Currently, the majority of research investigating possible genetic causes of obesity is focused on nuclear DNA (nDNA). While this has lead to the development of numerous animal models, it is apparent the etiology of obesity is more complex than single gene mutations. Recently it has also been suggested that mitochondrial DNA (mtDNA) mutations sustained during evolution as a consequence of our prehistoric environment may influence individual propensity and risk of disease. Contemporary human populations are no longer faced with the challenges of our ancestors such as …
Mitochondrial Genetics And Cellular Metabolism Regulate Tumorigenicity And Metastatic Potential, Kyle Paul Feeley
Mitochondrial Genetics And Cellular Metabolism Regulate Tumorigenicity And Metastatic Potential, Kyle Paul Feeley
All ETDs from UAB
Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors combine to influence an individual's predilection for breast cancer and related metastatic tumor formation. The genetic component, in particular, has become the focus of many emergent studies. A renewed focus on cancer metabolism and the Warburg effect has similarly cast a spotlight on the role, if any, of the mitochondrion in directing disease progression. Analysis of the direct contribution of mitochondrial DNA on tumorigenicity is made possible through the use of mitochondrial-nuclear exchange (MNX) mice in which nuclei from normal FVB mice (the background strain of the tg: …
Mitochondrial Dysfunction In Response To Neurotoxins And The Role Of Mitophagy, Samantha Giordano
Mitochondrial Dysfunction In Response To Neurotoxins And The Role Of Mitophagy, Samantha Giordano
All ETDs from UAB
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Two major factors in both familial and sporadic PD are mitochondrial dysfunction and insufficient autophagy. My thesis research focuses on the interplay between these activities in PD. To investigate the common and differential effects of PD-inducing neurotoxins on mitochondrial bioenergetics and their relationships to cell survival, we used an in vitro culture system, differentiated dopaminergic SH-SY5Y neuroblastoma cells. We found that the neurotoxins rotenone, 1-methyl-4- phenylyridinium (MPP+) and 6-hydroxydopamine (6-OHDA), decreased mitochondrial respiration and induced cell death in these cells. The extent and characteristics of mitochondrial dysfunction in response to …
O-Linked Beta-N-Acetylglucosamine (O-Glcnac) And The Mitochondrion, Christopher Calderon
O-Linked Beta-N-Acetylglucosamine (O-Glcnac) And The Mitochondrion, Christopher Calderon
All ETDs from UAB
O-linked beta-N-acetylglucosamine (O-GlcNAc) is a dynamic and ubiquitous posttranslational modification of serine and threonine residues on nuclear and cytoplasmic proteins. O-GlcNAc has emerged as an important regulator of cellular processes such as cell signaling, transcription, translation, apoptosis, and cell cycle regulation, among others. O-GlcNAc is thought to be a contributor to pathologies such as hyperglycemia and insulin resistance. O-GlcNAc has been viewed as an indicator of cellular energy levels and is associated with diabetic complications under nutrient excess. Other studies have shown that a variety of stress stimuli increase the levels of protein O-GlcNAc in mammalian cells, and this increase …
The Hypometabolic Actions Of Hydrogen Sulfide In Mammalian Systems, Asaf Stein
The Hypometabolic Actions Of Hydrogen Sulfide In Mammalian Systems, Asaf Stein
All ETDs from UAB
In recent years, hydrogen sulfide (H2S) has been identified as a ubiquitous cell signaling molecule. In addition to its diverse physiological roles, H2S has emerged as a possible drug therapy, with a wide range of applications. Along with cytoprotective effects in pathological states such as ischemia-reperfusion injury, H2S has been shown to decrease aerobic metabolism in a reversible manner. This dissertation is focused on exploring H2S-induced hypometabolism and the implications therein for human health and disease. We have shown that rats exposed to 80 ppm H2S gas in combination with low oxygen (10.5% O2) for 6 hr exhibit decreases in …
Targeting Mitochondrial Function In Diabetic Nephropathy, Colin Reily
Targeting Mitochondrial Function In Diabetic Nephropathy, Colin Reily
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TARGETING MITOCHONDRIAL FUNCTION IN DIABETIC NEPHROPATHY The incidence of diabetes has increased to epidemic proportions over the last 50 years, due to a complex interaction of lifestyle and dietary factors. Changes in physical activity, caloric intake, and the composition of foods consumed over the last century are thought to interact with metabolic syndrome prone subpopulations leading ultimately to diabetes. It is widely accepted that chronic hyperglycemia in the blood characterizes the diabetic condition. Since the discovery of insulin therapy in the first half of the 20th century, diabetics have extended their lifespan considerably, but at the cost of increased morbitity …
Mitochondrial Morphology And Function In Neuronal Cells Under Stress, Lonnie Schneider
Mitochondrial Morphology And Function In Neuronal Cells Under Stress, Lonnie Schneider
All ETDs from UAB
Neurodegenerative disease encompasses a wide range of conditions and pathologies that can manifest at any age depending on the etiology. A major factor in both early onset and age-related neurodegeneration is mitochondrial dysfunction. To investigate how mitochondrial bioenergetics is affected by cellular stress, we used an in vitro culture system to examine mitochondrial function in response to oxidative stress. We also studied an in vivo model of neuronal ceroid lipofuscinosis to determine the impact of deficient autophagy-lysosomal activity on mitochondrial morphology, composition and function. In vitro we found that retinoic acid-induced differentiation of dopaminergic neuroblastoma SH-SY5Y cells exhibited increased mitochondrial …
The Role Of Vpr-1 Msp Signaling In C. Elegans, Sung Min Han
The Role Of Vpr-1 Msp Signaling In C. Elegans, Sung Min Han
All ETDs from UAB
In C. elegans, the major sperm protein (MSP) is the most abundant protein in sperm and functions as an intracellular cytoskeleton protein and a secreted extracellular signal that induces oocyte maturation and sheath contraction. Evolutionarily, MSP domain-containing proteins originate from the VAPs (VAMP/synaptobrevin-associated proteins), which comprise a highly conserved protein family with an MSP domain at the N-terminus and a transmembrane domain at the C-terminus. I have been studying the signaling role of VAP MSP domains using the C. elegans model system. In collaboration with Hugo Bellen's lab at Baylor College of Medicine, we have shown that C. elegans, Drosophila, …
Mitochondrial Genetics And Function In Cardiovascular Disease Susceptibility, Jessica L. Brenneman
Mitochondrial Genetics And Function In Cardiovascular Disease Susceptibility, Jessica L. Brenneman
All ETDs from UAB
While progress has been made in understanding the development and progression of cardiovascular disease (CVD), the mechanisms of CVD risk and initiation are not completely understood. It is widely accepted that CVD is the result of a combination of genetic and environmental factors but it is not known why some populations with otherwise similar risk factors appear more susceptible to CVD than others. It is also known that different strains of laboratory mice have distinct susceptibilities to CVD development. For example, C3H mice are resistant to diet induced atherogenesis whereas C57 animals are susceptible. We have also found that the …
Structural And Mechanistic Studies On Er Upr Sensor Perk And Mitochondrial Translocon Element Tim44, Wenjun Cui
Structural And Mechanistic Studies On Er Upr Sensor Perk And Mitochondrial Translocon Element Tim44, Wenjun Cui
All ETDs from UAB
The unfolded protein response is one mechanism utilized by endoplasmic reticulum (ER) to maintain the homeostasis between ER protein folding machinery and ER proteins. UPR is induced by three ER transmembrane sensors: IRE1, ATF6 and PERK. PKR-like ER kinase (PERK) can sense the ER stress signal through its luminal domain to activate its cytoplasmic kinase domain catalytic activity. PERK kinase domain belongs to the eIF2α family. Members in this family are activated after being autophosphorylated at their activation loops and then specifically phosphorylate eIF2α at its Ser51 position. Phosphorylation of eIF2α can shutdown the cytosol protein translation from the initiation …
The Role Of Mitochondrial Oxidative Stress In Cardiovascular Disease Development, Corey Michael Harrison
The Role Of Mitochondrial Oxidative Stress In Cardiovascular Disease Development, Corey Michael Harrison
All ETDs from UAB
An estimated 70 million Americans have one or more types of cardiovascular disease (CVD). Although the sequence of events leading to CVD are still controversial, there is a general consensus that atherosclerotic lesions result from oxidative stress associated with risk factor. For this study, it was hypothesized that endogenous mitochondrial oxidative stress would influence susceptibility to atherogenesis and mitochondrial damage mediated by CVD risk factor exposure. To test this hypothesis, atherosclerotic lesion formation, oxidant stress, and mitochondrial DNA damage were assessed in hypercholestoremic mice (apolipoprotein E null - apoE -/- SOD2 +/+) and mice with significantly decreased levels of the …
Intracellular Distribution Of Glycogen Synthase Kinase-3beta In The Brain, Johanna C. Gandy
Intracellular Distribution Of Glycogen Synthase Kinase-3beta In The Brain, Johanna C. Gandy
All ETDs from UAB
The widely distributed serine/threonine kinase glycogen synthase kinase 3beta is well known for its multiple functions in the health brain tissue, which include cell fate, neuronal growth and remodeling, synaptic plasticity, and neuroinflammation. However much of GSK3beta focuses on its abnormal functions in neurological disorders like Alzheimer's Disease and psychiatric disorders. To maintain normal GSK3beta function in the brain, this constitutively active kinase must be strictly regulated. Many factors within the cell work together to influence GSK3beta activity. Two ways to regulate GSK3beta activity are through phosphorylation by upstream kinases or the formation of protein complexes that block substrate binding. …
Protein Modifications And The Response To Oxidized Lipids In Cardiovascular Cells, Ashlee Higdon
Protein Modifications And The Response To Oxidized Lipids In Cardiovascular Cells, Ashlee Higdon
All ETDs from UAB
Free radical catalyzed oxidation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid is increased in cardiovascular disease states, including atherosclerosis and heart failure. Oxidized lipids have been extensively studied and found to recapitulate several key steps in atherogenesis. However, clinical trials with antioxidants such as alpha-tocopherol have been less promising than originally predicted. Now appreciated as more than just biomarkers of disease, lipid peroxidation products have been shown to have roles in pathogenesis as well as physiology. Of particular interest are reactive lipid species that possess electrophilic carbonyls enabling them to act in a receptor-independent manner. To date, the …
Role Of Heme Oxygenase-1 In Acute Kidney Injury, Subhashini Bolisetty
Role Of Heme Oxygenase-1 In Acute Kidney Injury, Subhashini Bolisetty
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Acute kidney injury (AKI), defined as the rapid loss of kidney function, is often seen in the setting of multiple organ failure in critically ill patients. Lack of established therapeutic approaches to overcome AKI has lead to unacceptably high incidence of morbidity and mortality in these patients. The molecular mechanisms that lead to AKI often have oxidative stress as a common pathogenic event. The kidney responds by prompt induction of its own anti-oxidant machinery including the highly inducible, anti-inflammatory and anti-apoptotic gene-heme oxygenase-1 (HO-1). This microsomal enzyme degrades pro-oxidant heme, which is released from heme proteins. The cytoprotective properties of …
The Effects Of Environmental Ozone Exposure On Vascular Function, Oxidative Stress, And Atherosclerosis, Gin Chuang
The Effects Of Environmental Ozone Exposure On Vascular Function, Oxidative Stress, And Atherosclerosis, Gin Chuang
All ETDs from UAB
Exposure to air pollutants are known to induce airway inflammation, decrease lung function, and worsen existing pulmonary conditions such as asthma. Additionally, air pollutant exposure has also been shown to impact cardiovascular health. Although these pollutant-induced cardiovascular effects were considered to be mediated by the direct action of pollutants upon the cardiovascular tissue and/or the indirect release of pro-inflammatory factors into the circulation, the relative contribution of the two pathways remained equivocal. Recently, several epidemiology studies associated ozone exposure with cardiovascular mortalities. However, relatively few studies to date have examined ozone in this context. In order to address our hypothesis …
Chronic Alcohol Consumption Promotes Opening Of The Mitochondrial Permeability Transition Pore And Increases Mitochondrial Injury In Liver, Adrienne Lester King
Chronic Alcohol Consumption Promotes Opening Of The Mitochondrial Permeability Transition Pore And Increases Mitochondrial Injury In Liver, Adrienne Lester King
All ETDs from UAB
Alcoholic liver disease is a serious public health concern. In particular, the mitochondrion is a specific target of ethanol toxicity and much of the damage can be related to unregulated Ca2+ homeostasis and oxidative stress which are key players in the induction of the mitochondrial permeability transition pore (MPTP) within the organelle. The mechanism behind the induction of the MPTP remains elusive. Therefore, this body of work will provide insight on what effects chronic alcohol consumption has on mitochondrial dysfunction with an emphasis on the MPTP. Chapter 2: Assessment of mitochondrial dysfunction arising from treatment with hepatotoxicants provides a description …
The Role Of Mitochondria And Plasma Membrane Ca2+ Transport Systems In Ca2+-Dependent Glutamate Release From Rat Cortical Astrocytes, Reno Cervo Reyes
The Role Of Mitochondria And Plasma Membrane Ca2+ Transport Systems In Ca2+-Dependent Glutamate Release From Rat Cortical Astrocytes, Reno Cervo Reyes
All ETDs from UAB
Astrocytes, a type of glial cell in the central nervous system, are recognized for their support roles to neurons. They supply neurons with metabolites, maintain ion homeostasis and clear the synaptic space of neurotransmitters. However, it has been found that some astrocytes have receptors for neurotransmitter and neuroligands, exhibit Ca2+ excitability when stimulated via these receptors, and secrete gliotransmitters as an output of this Ca2+ excitability. In the Ca2+-dependent release of glutamate, it has been shown that the endoplasmic reticulum is the predominant source and the extracellular space is the auxiliary source of free Ca2+ necessary for triggering exocytosis. Because …