Ca2+-Dependent and Ca2+-Independent ATP Release in Astrocytes

[...]unlike the mechanism of neurotransmission via quantal exocytosis (Katz, 1959, 1969; Augustine and Neher, 1992; Neher, 1998; Sudhof, 2004; Pankratov et al., 2006, 2007; Sudhof and Rothman, 2009), the mechanisms by which ATP is released remain controversial. Because ATP is easily hydrolyzed, monitoring its real-time release is a challenge. In the Ca2+-independent pathway, ATP is released through channels expressed on the astrocyte plasma membrane, such as the swelling-induced anion channel, connexin hemichannels activated by lower Ca2+ concentrations, and ionotropic purinergic receptor channels. Since P2X7 itself is not mechanosensor, we hypothesize that a mechanosensor [such as piezo 1 protein (Zhao et al., 2018)] binds P2X7 and “transactivates” mechanical force to activate P2X7 [One recent example of protein-transactivation is that a voltage-sensor channel activates another binding protein of vesicle fusion-pore (Chai et al., 2017)]. [...]the large ATP release via MARA would recruit microglia, leading to protective or pathological pathways (Dou et al., 2012). [...]we propose that MARA could be a mechanism underlying brain diseases such as those associated with hypoxia/ischemia and trauma, as well as other neurological disorders (Parkinson's disease, Alzheimer's disease, and epilepsy) (Figure 1D).