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Synapses
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Small-molecule neurotransmitters, or simply neurotransmitters, are synthesized mainly in axon terminals and are actively packaged into small electron-lucent vesicles, about 40 nm in diameter, by transporters driven by a H+ electrochemical potential gradient. This gradient is established by a vacuolar-type H+-ATPase (V-ATPase) which uses the energy from ATP hydrolysis to pump H+ (protons) into vesicles. This results in a lower pH inside the vesicle and in a positive voltage of tens of millivolts or more with respect to the cytoplasm. The resulting electrochemical potential gradient for H+ is used to accumulate various substances inside the vesicle. The vesicles are released into the synaptic cleft at active zones through exocytosis (Section 1.1.3) mediated by the inflow of Ca2+ resulting from depolarization of the presynaptic terminal, as in the NMJ. However, there is evidence that in some cases neurotransmitters may be released by exocytosis from the axoplasm directly into the synaptic cleft. Vesicles may be round or flat in shape. It is believed that the former are found in excitatory synapses, whereas the latter are found in inhibitory synapses.
Role of Mitochondrial Injury During Oxidative Injury to Hepatocytes: Evidence of a Mitochondrial Permeability Transition by Laser Scanning Confocal Microscopy
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Anna-Liisa Nieminen, Roberto Imberti, Alice K. Saylor, Samuel A. Tesfai, Brian Herman, John J. Lemasters
In freshly isolated rat hepatocytes, cyanide caused progressive cell killing over 2½ hours (Figure 1). Fructose protected completely against this cell killing. To test the hypothesis that protection was mediated by glycolytic ATP generation, we examined the effect of the mitochondrial uncoupler, CCCP, on fructose protection. CCCP collapses the mitochondrial proton electrochemical gradient and stimulates the mitochondrial F1F0-ATPase. Thus, if fructose protection is mediated through intracellular ATP generation, accelerated ATP hydrolysis induced by CCCP should block fructose protection. This is what was found experimentally (Figure 1). To further test the hypothesis that cell killing is ATP-linked, we evaluated the effect of oligomycin. Oligomycin is an inhibitor of the mitochondrial F1F0- ATPase. By itself, oligomycin is cytotoxic,3 but in the presence of fructose and CCCP, oligomycin should block accelerated ATP hydrolysis and prevent cell killing. Again, the experiments confirmed this expectation (Figure 1). In parallel experiments, we measured cellular ATP levels. Cyanide caused ATP to fall below measurable levels (Figure 2). Fructose partially restored ATP, but CCCP blocked the fructose-induced restoration of ATP, an effect reversed by oligomycin. In every case a positive correlation was observed between preservation of cell viability and ATP.
Endosomal and Lysosomal Electrophysiology
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Xiaoli Zhang, Mingxue Gu, Meiqin Hu, Yexin Yang, Haoxing Xu
H+: A hallmark feature of the lysosome is its acidic pH (pH 4.6) in the lumen, which is required for the activity of most lysosome hydrolases (Kolter and Sandhoff, 2005; Mindell, 2012). During endosome maturation, the V-ATPase is responsible for decreasing luminal pH from 6.5 in early endosomes to 4.6 in late endosomes and lysosomes (LELs) (Huotari and Helenius, 2011). Disruption of lysosomal pH gradient using V-ATPase inhibitors (e.g., bafilomycin-A1) or protonophores results in accumulation of the endocytic and autophagic cargos (Kawai et al., 2007; Padman et al., 2013). In addition, lysosomal pH or V-ATPase regulates other lysosomal functions, including autophagosome-lysosome fusion (Kawai et al., 2007; Mauvezin and Neufeld, 2015) and nutrient sensing (Zoncu et al., 2011).
RANKL: A therapeutic target for bone destruction in rheumatoid arthritis
Published in Modern Rheumatology, 2018
Sakae Tanaka, Yoshiya Tanaka, Naoki Ishiguro, Hisashi Yamanaka, Tsutomu Takeuchi
Osteoclasts possess many cellular machineries specifically developed for bone resorption [12] (Figure 1). When osteoclasts attach to the bone surface via αvβ3 integrin, they become highly polarized and form a ring-like adhesion structure rich in filamentous actin (F-actin), referred to as the ‘sealing zone’. The space between the cells and the bone matrix constitutes the bone-resorbing compartment (‘resorption lacunae’ or ‘Howship’s lacunae’). Osteoclasts produce proteolytic enzymes including cathepsin K and matrix metalloproteinase-9, which are stored in lysosomes and then transported towards the apical side of the cells and secreted into the resorption lacunae through the ruffled border, with important roles in bone matrix degradation. Osteoclasts acidify this compartment by secreting protons via proton pumps (vacuolar type H+-ATPase) located on the ruffled border membrane, and the low pH (pH 3–4) of the compartment leads to bone demineralization [12]. Osteoclasts express the G protein-coupled calcitonin receptor, and calcitonin negatively regulates osteoclast activity [12].
ATP6V1H facilitates osteogenic differentiation in MC3T3-E1 cells via Akt/GSK3β signaling pathway
Published in Organogenesis, 2019
Fusong Jiang, Haojie Shan, Chenhao Pan, Zubin Zhou, Keze Cui, Yuanliang Chen, Haibo Zhong, Zhibin Lin, Nan Wang, Liang Yan, Xiaowei Yu
ATP6V1H (V-type proton ATPase subunit H) encodes the subunit H of V-type proton ATPase,4 and plays crucial roles in various biological processes, including a key role in regulating functions of osteoblastic cells.5 Through interacting with TGF-β receptor I and AP-2 complex, ATP6V1H regulates the proliferation and differentiation of bone marrow stromal cells.6 In zebrafish, ATP6V1H loss-of-function mutants led to severe reduced number of mature-calcified bone cells, demonstrating that ATP6V1H could regulate bone formation.5 In addition, ATP6V1H± knockout mice showed significantly decreased bone remodeling, bone matrix loss and impaired bone formation.7
The role of lysosomal ion channels in lysosome dysfunction
Published in Inhalation Toxicology, 2021
Rebekah L. Kendall, Andrij Holian
Ion channels play a crucial role in maintaining the necessary pH levels for lysosomal function, as the ionic homeostasis necessary for lysosome acidification comes from the progressive proton pump activity of the vacuolar-type ATPase (V-ATPase) in conjunction with ionic movement by other channels (Mindell 2012). The V-ATPase is similar in many ways to the F-type ATPase found in the inner mitochondrial membrane, a rotary proton transport machine comprised of multiple subunits organized into two large domains, V1 and V0. The peripheral domain, V1, catalyzes the cytosolic hydrolysis of ATP, providing the energy needed to pump protons into the lumen. The membrane-embedded domain, V0, houses the rotary component that facilitates the transport of protons from the cytosol into the lumen (Mindell 2012). The V-ATPase proton pumping action is irreversible and highly efficient, moving 2-4 protons into the lysosome lumen per ATP hydrolyzed (Mindell 2012; Colacurcio and Nixon 2016). The coupling ratio of protons to ATP is dynamic and allows the lysosome to react to a variety of substrates while maintaining an optimal pH that can change depending on nutrient needs of the cell (Li et al. 2019). This ability to maintain an optimal pH is dependent on the function of other lysosomal ion channels and membrane potential. The H+ concentration within the lysosome is balanced by an influx and efflux of ions to counter the charges contained within the lumen and maintain the lysosomal membrane potential necessary for continued V-ATPase function (Xu and Ren 2015; Kissing et al. 2018). A more comprehensive understanding of V-ATPase activity and its role in lysosome function can be found in these reviews (Mindell 2012; Cotter et al. 2015; Kissing et al. 2018).