Astrocyte calcium waves propagate proximally by gap junction and distally by extracellular diffusion of ATP released from volume-regulated anion channels

Abstract

Wave-like propagation of [Ca2+]i increases is a remarkable intercellular communication characteristic in astrocyte networks, intercalating neural circuits and vasculature. Mechanically-induced [Ca2+]i increases and their subsequent propagation to neighboring astrocytes in culture is a classical model of astrocyte calcium wave and is known to be mediated by gap junction and extracellular ATP, but the role of each pathway remains unclear. Pharmacologic analysis of time-dependent distribution of [Ca2+]i revealed three distinct [Ca2+]i increases, the largest being in stimulated cells independent of extracellular Ca2+ and inositol 1,4,5-trisphosphate-induced Ca2+ release. In addition, persistent [Ca2+]i increases were found to propagate rapidly via gap junctions in the proximal region, and transient [Ca2+]i increases were found to propagate slowly via extracellular ATP in the distal region. Simultaneous imaging of astrocyte [Ca2+]i and extracellular ATP, the latter of which was measured by an ATP sniffing cell, revealed that ATP was released within the proximal region by volume-regulated anion channel in a [Ca2+]i independent manner. This detailed analysis of a classical model is the first to address the different contributions of two major pathways of calcium waves, gap junctions and extracellular ATP.

Transient Cell Membrane Disruptions induce Calcium Waves in Corneal Keratocytes

“…Alternatively, we have reported that elevated Ca ++ increases gap junction connectivity between corneal epithelial cells 29 . In astrocytes, mechanically-induced Ca ++ ion increases and their subsequent propagation to neighboring cells were found to have two distinct patterns: (1) persistent increases were found to propagate rapidly via gap junctions in the www.nature.com/scientificreports www.nature.com/scientificreports/ proximal region, and (2) transient increases were found to propagate slowly via extracellular ATP in the distal region 11 . It has also been reported that forced expression of gap junction connexins successfully enables gap junction-deficient cell lines to propagate intercellular Ca ++ waves, stimulating secretion of ATP 5-to 15-fold from the cells 30 .…”

“…Gap junctions and ATP have both been shown to promote intercellular calcium wave propagation 11 . Gap junctions are specialized plasma membrane structures that provide a communication pathway among adjacent cells, facilitating direct exchange of small molecules (<1000 Da) including ions, metabolites and second messengers (e.g., calcium, glucose, cAMP, cGMP, IP3) 12 .…”

Piezo1 regulates calcium oscillations and cytokine release from astrocytes

“…ATP is also important in the propagation of Ca 2+ waves through astrocyte networks (Fujii, Maekawa, & Morita, 2017). Moreover, vasoactive substance release is regulated by astrocytic Ca 2+ waves and ATP-induced Ca 2+ release from intracellular stores within astrocytes (Metea & Newman, 2006).…”

An astrocytic basis of caloric restriction action on the brain plasticity

“…The role of gap-junctions in K + spatial buffering has been suggested (Kofuji and Newman, 2004;Ma et al, 2016). Ca 2+ events propagate in the astrocytic network through two major mechanisms -extracellular, involving neurotransmitter release, and intracellular, through the gap-junctions (Fujii et al, 2017;Semyanov, 2019). Gap-junction coupling has two possibilities for plasticity: (1) change in the number of connections and…”

“…3f). Such changes in Ca 2+ activity arguably reflect cell uncoupling in the astrocytic network and the inability of Ca 2+ events to propagate through the gap-junctions to the neighboring cells (Fujii et al, 2017). The integral of astrocytic Ca 2+ activity was unchanged in CR (p = 0.27, Mann-Whitney test with control, Fig.…”