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Exocytosis of ATP from astrocyte progenitors modulates spontaneous Ca2+ oscillations and cell migration.

ABSTRACT: In the mature central nervous system (CNS) regulated secretion of ATP from astrocytes is thought to play a significant role in cell signaling. Whether such a mechanism is also operative in the developing nervous system and, if so, during which stage of development, has not been investigated. We have tackled this question using cells derived from reconstituted neurospheres, as well as brain explants of embryonic mice. Here, we show that in both models of neural cell development, astrocyte progenitors are competent for the regulated secretion of ATP-containing vesicles. We further document that this secretion is dependent on cytosolic Ca(2+) and the v-SNARE system, and takes place by exocytosis. Interference with ATP secretion alters spontaneous Ca(2+) oscillations and migration of neural progenitors. These data indicate that astrocyte progenitors acquire early in development the competence for regulated secretion of ATP, and that this event is implicated in the regulation of at least two cell functions, which are critical for the proper morphogenesis and functional maturation of the CNS.

SUBMITTER: Striedinger K

PROVIDER: S-EPMC2617704 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Exocytosis of ATP from astrocyte progenitors modulates spontaneous Ca2+ oscillations and cell migration.

Striedinger Katharine K Meda Paolo P Scemes Eliana E

Glia 20070401 6

In the mature central nervous system (CNS) regulated secretion of ATP from astrocytes is thought to play a significant role in cell signaling. Whether such a mechanism is also operative in the developing nervous system and, if so, during which stage of development, has not been investigated. We have tackled this question using cells derived from reconstituted neurospheres, as well as brain explants of embryonic mice. Here, we show that in both models of neural cell development, astrocyte progeni ...[more]

PMID: 17309060

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Project description:IntroductionCa2+ release from sarcoplasmic reticulum (SR) is known to contribute to automaticity via the cytoplasmic Na+-Ca2+ exchanger (NCX). Mitochondria participate in Ca2+ cycling. We studied the role of mitochondrial Ca2+ flux in ventricular spontaneous electrical activity.MethodsSpontaneously contracting mouse embryonic stem cells (ESC)-derived ventricular cardiomyocytes (CMs) were differentiated from wild type and ryanodine receptor type 2 (RYR2) knockout mouse ESCs and differentiated for 19-21 days. Automaticity was also observed in human induced pluripotent stem cell (hiPSC)-derived ventricular CMs differentiated for 30 days, and acute isolated adult mouse ventricular cells in ischemic simulated buffer. Action potentials (APs) were recorded by perforated whole cell current-clamp. Cytoplasmic and mitochondrial Ca2+ transients were determined by fluorescent imaging.ResultsIn mouse ESC-derived ventricular CMs, spontaneous beating was dependent on the L-type Ca2+ channel, cytoplasmic NCX and mitochondrial NCX. Spontaneous beating was modulated by SR Ca2+ release from RYR2 or inositol trisphosphate receptors (IP3R), the pacemaker current (If) and mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU). In RYR2 knockout mouse ESC-derived ventricular CMs, mitochondrial Ca2+ flux influenced spontaneous beating independently of the SR Ca2+ release from RYR2, and the mitochondrial effect was dependent on IP3R SR Ca2+ release. Depolarization of mitochondria and preservation of ATP could terminate spontaneous beating. A contribution of mitochondrial Ca2+ flux to automaticity was confirmed in hiPSC-derived ventricular CMs and ischemic adult mouse ventricular CMs, confirming the findings across species and cell maturity levels.ConclusionsMitochondrial and sarcolemma NCX fluxes are required for ventricular automaticity. Mitochondrial Ca2+ uptake plays a modulatory role. Mitochondrial Ca2+ uptake through MCU is influenced by IP3R-dependent SR Ca2+ release.

Project description:Communication between neuronal and glial cells is important for many brain functions. Astrocytes can modulate synaptic strength via Ca(2+)-stimulated release of various gliotransmitters, including glutamate and ATP. A physiological role of ATP release from astrocytes was suggested by its contribution to glial Ca(2+)-waves and purinergic modulation of neuronal activity and sleep homeostasis. The mechanisms underlying release of gliotransmitters remain uncertain, and exocytosis is the most intriguing and debated pathway. We investigated release of ATP from acutely dissociated cortical astrocytes using "sniff-cell" approach and demonstrated that release is vesicular in nature and can be triggered by elevation of intracellular Ca(2+) via metabotropic and ionotropic receptors or direct UV-uncaging. The exocytosis of ATP from neocortical astrocytes occurred in the millisecond time scale contrasting with much slower nonvesicular release of gliotransmitters via Best1 and TREK-1 channels, reported recently in hippocampus. Furthermore, we discovered that elevation of cytosolic Ca(2+) in cortical astrocytes triggered the release of ATP that directly activated quantal purinergic currents in the pyramidal neurons. The glia-driven burst of purinergic currents in neurons was followed by significant attenuation of both synaptic and tonic inhibition. The Ca(2+)-entry through the neuronal P2X purinoreceptors led to phosphorylation-dependent down-regulation of GABAA receptors. The negative purinergic modulation of postsynaptic GABA receptors was accompanied by small presynaptic enhancement of GABA release. Glia-driven purinergic modulation of inhibitory transmission was not observed in neurons when astrocytes expressed dn-SNARE to impair exocytosis. The astrocyte-driven purinergic currents and glia-driven modulation of GABA receptors were significantly reduced in the P2X4 KO mice. Our data provide a key evidence to support the physiological importance of exocytosis of ATP from astrocytes in the neocortex.

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Exocytosis of ATP from astrocyte progenitors modulates spontaneous Ca2+ oscillations and cell migration.

Publications

Exocytosis of ATP from astrocyte progenitors modulates spontaneous Ca2+ oscillations and cell migration.

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