Signal transduction in astrocytes: Localization and release of inorganic polyphosphate

Abstract

Inorganic polyphosphate (polyP) is present in every cell and is highly conserved from primeval times. In the mammalian cells, polyP plays multiple roles including control of cell bioenergetics and signal transduction. In the brain, polyP mediates signaling between astrocytes via activation of purinergic receptors, however, the mechanisms of polyP release remain unknown. Here we report identification of polyP‐containing vesicles in cortical astrocytes and the main triggers that evoke vesicular polyP release. In cultured astrocytes, polyP was localized predominantly within the intracellular vesicular compartments which express vesicular nucleotide transporter VNUT (putative ATP‐containing vesicles), but not within the compartments expressing vesicular glutamate transporter 2 (VGLUT2). The number of lysosomes which contain polyP was dependent on the conditions of astrocytes. Release of polyP from a proportion of lysosomes could be induced by calcium ionophores. In contrast, polyP release from the VNUT‐containing vesicles could be triggered by various physiological stimuli, such as pH changes, polyP induced polyP release and other stimuli which increase [Ca2+]i. These data suggest that astrocytes release polyP predominantly via exocytosis from the VNUT‐containing vesicles. © 2018 Wiley Periodicals, Inc.

Inorganic polyphosphate is produced and hydrolyzed in F0F1-ATP synthase of mammalian mitochondria

“…It also should be noticed that we observed the activity of F 0 F 1 -ATPase in millimolar concentration (Figure 2 and 3). Although the average polyP concentration in the brain is 50-70 mM [3], polyP is highly compartmentalized [13,15,18] and concentration of polyP in some of the compartments (such as mitochondria) can reach millimolar level. Measurements of polyP in isolated mitochondria using polyP-DAPI fluorescence.…”

“…Moreover, the similarity in chemical structure between ATP (three orthophosphates) and polyP (multiple orthophosphates) spreads over to further similarity in the function they both exert in physiology. Thus, polyP plays an important signaling role in the mammalian brain: located to and released from ATP-containing vesicles [13]; it activates neurons and astrocytes through P2Y1 (known to be mostly specific to ATP and ADP) purinoreceptors [14,15]. Interestingly, polyP is shown to be an energy source for extracellular ATP production [16,17].…”

Inorganic Polyphosphate Regulates AMPA and NMDA Receptors and Protects Against Glutamate Excitotoxicity via Activation of P2Y Receptors

“…One of the oldest polymers in the evolution of the living matter is the inorganic polyphosphate (PolyP). It plays an essential role in bacteria, yeast, and protozoa, but is also presented in relatively high concentration in the mammalian brain, up to 50 M, where it acts as a gliotransmitter (Lorenz et al, 1997;Holmström et al, 2013;Angelova et al, , 2018. As seen by the relatively small number of publications in this field to date, the function of this polymer is largely underestimated, especially for the brain.…”

“…Potentially, PolyP can play multiple roles in the CNS (Kumble and Kornberg, 1995;Angelova et al, 2016;Cremers et al, 2016;Müller et al, 2017). For example, in astrocytes it is localized in mitochondria, lysosomes, and vesicular nucleotide transporter (VNUT)-containing vesicles (Abramov et al, 2007;Pavlov et al, 2010;Holmström et al, 2013;Angelova et al, 2018). PolyP is released from lysosomes or VNUT vesicles by exocytosis, which leads to the development of calcium waves Angelova et al, 2018).…”

“…For example, in astrocytes it is localized in mitochondria, lysosomes, and vesicular nucleotide transporter (VNUT)-containing vesicles (Abramov et al, 2007;Pavlov et al, 2010;Holmström et al, 2013;Angelova et al, 2018). PolyP is released from lysosomes or VNUT vesicles by exocytosis, which leads to the development of calcium waves Angelova et al, 2018). Structurally, PolyP consists of long chains of only orthophosphate residues, but despite such a simple composition it is able to activate P2Y1 receptors, stimulating the activation of phospholipase C and inducing the release of Ca 2ϩ from the endoplasmic reticulum via the IP 3 receptors Dinarvand et al, 2014).…”