Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP‐independent control of ATP‐sensitive K<sup>+</sup> channels

Ainscow, Edward; Mirshamsi, Shirin; Tang, Teresa; Ashford, M. L. J.; Rutter, Guy A.

doi:10.1113/jphysiol.2002.022434

Cited by 176 publications

(171 citation statements)

References 52 publications

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“…It is generally assumed that ATP freely distributes in the cytosol at a concentration of 1-10 mM 52 and that the opening of channels across the plasma membrane would allow for its passive diffusion into the extracellular space. 53 Our observations are at odds with this view.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of ATP secretion during immunogenic cell death

et al. 2013

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The immunogenic demise of cancer cells can be induced by various chemotherapeutics, such as anthracyclines and oxaliplatin, and provokes an immune response against tumor-associated antigens. Thus, immunogenic cell death (ICD)-inducing antineoplastic agents stimulate a tumor-specific immune response that determines the long-term success of therapy. The release of ATP from dying cells constitutes one of the three major hallmarks of ICD and occurs independently of the two others, namely, the pre-apoptotic exposure of calreticulin on the cell surface and the postmortem release of high-mobility group box 1 (HMBG1) into the extracellular space. Pre-mortem autophagy is known to be required for the ICD-associated secretion of ATP, implying that autophagy-deficient cancer cells fail to elicit therapy-relevant immune responses in vivo. However, the precise molecular mechanisms whereby ATP is actively secreted in the course of ICD remain elusive. Using a combination of pharmacological screens, silencing experiments and techniques to monitor the subcellular localization of ATP, we show here that, in response to ICD inducers, ATP redistributes from lysosomes to autolysosomes and is secreted by a mechanism that requires the lysosomal protein LAMP1, which translocates to the plasma membrane in a strictly caspase-dependent manner. The secretion of ATP additionally involves the caspase-dependent activation of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)-mediated, myosin II-dependent cellular blebbing, as well as the opening of pannexin 1 (PANX1) channels, which is also triggered by caspases. Of note, although autophagy and LAMP1 fail to influence PANX1 channel opening, PANX1 is required for the ICD-associated translocation of LAMP1 to the plasma membrane. Altogether, these findings suggest that caspase-and PANX1-dependent lysosomal exocytosis has an essential role in ATP release as triggered by immunogenic chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of ATP secretion during immunogenic cell death

et al. 2013

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“…The signals that originate by increased glucose can mediate cellular responses that could control the activity of orexigenic and anorexigenic neurons. It has been proposed that metabolic coupling between glia and hypothalamic neurons is carried out by lactate (Ainscow, Mirshamsi, Tang, Ashford, & Rutter, 2002; Thorens, 2012). For this reason and taking into account that tanycytes release lactate (Cortes‐Campos et al, 2011), we proposed that the lactate released by tanycytes in response to glucose is transferred to POMC neurons producing an increase in intracellular ATP, in a mechanism that is similar to that reported for pancreatic β‐cells (Meda & Schuit, 2013).…”

Section: Discussionmentioning

confidence: 99%

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

Barahona

Llanos

Recabal

et al. 2017

Glia

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Glucose is a key modulator of feeding behavior. By acting in peripheral tissues and in the central nervous system, it directly controls the secretion of hormones and neuropeptides and modulates the activity of the autonomic nervous system. GLUT2 is required for several glucoregulatory responses in the brain, including feeding behavior, and is localized in the hypothalamus and brainstem, which are the main centers that control this behavior. In the hypothalamus, GLUT2 has been detected in glial cells, known as tanycytes, which line the basal walls of the third ventricle (3V). This study aimed to clarify the role of GLUT2 expression in tanycytes in feeding behavior using 3V injections of an adenovirus encoding a shRNA against GLUT2 and the reporter EGFP (Ad‐shGLUT2). Efficient in vivo GLUT2 knockdown in rat hypothalamic tissue was demonstrated by qPCR and Western blot analyses. Specificity of cell transduction in the hypothalamus and brainstem was evaluated by EGFP‐fluorescence and immunohistochemistry, which showed EGFP expression specifically in ependymal cells, including tanycytes. The altered mRNA levels of both orexigenic and anorexigenic neuropeptides suggested a loss of response to increased glucose in the 3V. Feeding behavior analysis in the fasting‐feeding transition revealed that GLUT2‐knockdown rats had increased food intake and body weight, suggesting an inhibitory effect on satiety. Taken together, suppression of GLUT2 expression in tanycytes disrupted the hypothalamic glucosensing mechanism, which altered the feeding behavior.

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“…While glucose is the preferred carbon source in mammals, an energetic stress is an unlikely explanation of the poor endocrine differentiation observed in the absence of glucose for at least 4 reasons: first, the culture medium was supplemented with 10% fetal calf serum and a mix of amino acids, several of which are metabolized to generate ATP via the Krebs cycle (35); second, no difference in apoptotic nuclei could be observed in pancreases cultured in absence versus in presence of glucose; third, acinar cells developed properly whatever the extracellular glucose concentration was and fourth, glucose did not modify the extractable ATP content of the pancreatic explants. On the other hand, we do not exclude the possibility that subtle or compartmentalized changes in intracellular free ATP concentration (40,41), or in the levels of ADP or AMP may occur in response to glucose, and might regulate the activity of downstream targets including ATP-sensitive K ϩ channels (42) or AMP-activated protein kinase (43)(44)(45). These changes may in turn regulate cellular excitability and might affect gene expression through alterations in free Ca 2ϩ concentrations (46) or via the release of insulin and an action via beta cell insulin receptors (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation

Guillemain

Filhoulaud

Xavier

et al. 2007

Journal of Biological Chemistry

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Mature pancreatic cells develop during embryonic life from endodermal progenitors, and this developmental process depends on activation of a hierarchy of transcription factors. While information is available on mesodermal signals controlling pancreas development, little is known about environmental factors, such as the levels of nutrients including glucose, that may control this process. Here, we studied the effects of glucose on pancreatic cells development. We used an in vitro model where both endocrine and acinar cells develop from early pancreatic and duodenal homeobox-1 (PDX1)-positive embryonic pancreatic progenitors. We first showed that glucose does not have a major effect on global pancreatic cell proliferation, survival, and acinar cell development. On the other hand, glucose controlled both alpha and beta cell development. Specifically, the surface occupied by insulin-positive cells was 20-fold higher in pancreases cultured in presence than in absence of glucose, and this effect was dose-dependent over the range 0.5-10 mM. Glucose did not appear to control beta cell development by activating the proliferation of early progenitors or beta cells themselves but instead tightly regulated cell differentiation. Thus, glucose did not modify the pattern of expression of Neurogenin3, the earliest marker of endocrine progenitor cells, but was necessary for the expression of the transcription factor NeuroD, a direct target of Neurogenin3 known to be important for proper pancreatic endocrine cell development. We conclude that glucose interferes with the pancreatic endocrine cells development by regulating the transition between Ngn3 and upstream NeuroD.The mature mammalian pancreas contains two types of tissues: endocrine islet cells that produce hormones such as insulin (beta cells) and glucagon (alpha cells) and exocrine tissue whose acinar cells produce enzymes (e.g. amylase) that are secreted via the pancreatic ducts into the intestine. The pancreas originates from the dorsal and ventral regions of the foregut endoderm directly posterior to the stomach (1). Research conducted in the last few years has shed light on the processes controlling pancreatic endocrine-cell development. Studies of genetically engineered mice have identified a hierarchy of transcription factors regulating pancreas organogenesis and islet-cell differentiation (2, 3). The endodermal region committed to a pancreatic fate expresses the transcription factor Pancreatic and duodenal homeobox-1 (Pdx-1) (4, 5). The basic helix-loop-helix factor Neurogenin3 (Ngn3) is then expressed in epithelial pancreatic progenitor cells prior to endocrine differentiation (6). Ngn3 is necessary for pancreatic endocrine cell development, and Ngn3-deficient mice lack pancreatic endocrine cells (7). Lineage tracing experiments have also provided direct evidence that NGN3-expressing cells are islet progenitors (8). Thus, Ngn3 is a valuable marker for monitoring pancreatic endocrine-cell differentiation. NGN3 controls the expression of another member of the basic ...

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Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP‐independent control of ATP‐sensitive K⁺ channels

Cited by 176 publications

References 52 publications

Molecular mechanisms of ATP secretion during immunogenic cell death

Molecular mechanisms of ATP secretion during immunogenic cell death

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation

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Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP‐independent control of ATP‐sensitive K+ channels

Cited by 176 publications

References 52 publications

Molecular mechanisms of ATP secretion during immunogenic cell death

Molecular mechanisms of ATP secretion during immunogenic cell death

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation

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Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP‐independent control of ATP‐sensitive K⁺ channels