ATP and potassium ions: a deadly combination for astrocytes

Abstract

The ATP release channel Pannexin1 (Panx1) is self-regulated, i.e. the permeant ATP inhibits the channel from the extracellular space. The affinity of the ATP binding site is lower than that of the purinergic P2X7 receptor allowing a transient activation of Panx1 by ATP through P2X7R. Here we show that the inhibition of Panx1 by ATP is abrogated by increased extracellular potassium ion concentration ([K+]o) in a dose-dependent manner. Since increased [K+]o is also a stimulus for Panx1 channels, it can be expected that a combination of ATP and increased [K+]o would be deadly for cells. Indeed, astrocytes did not survive exposure to these combined stimuli. The death mechanism, although involving P2X7R, does not appear to strictly follow a pyroptotic pathway. Instead, caspase-3 was activated, a process inhibited by Panx1 inhibitors. These data suggest that Panx1 plays an early role in the cell death signaling pathway involving ATP and K+ ions. Additionally, Panx1 may play a second role once cells are committed to apoptosis, since Panx1 is also a substrate of caspase-3.

ATP release through pannexon channels

“…The entanglement between ATP and K þ on pannexons can also be observed in astrocytes and in brain slices as an approximation of in vivo conditions [94]. Additionally, in situ blockade of pannexons by ATP as determined by dye uptake in brain slices is present in wt mice and P2X7 KO mice, but not in Panx1 KO mice.…”

“…The interplay between ATP and K þ at pannexons has profound consequences in pathological conditions where damaged cells spill a series of pannexon activators onto adjacent healthy neighbouring cells [86,94]. Among these activators is K þ , which is a direct pannexon stimulant and also abolishes the negative feedback control on pannexonmediated ATP release.…”

“…Considering pannexons' large conductance and the permeability to all molecules up to 1.5 kDa, prolonged activation of pannexons would lead to the rundown of ionic gradients and loss of energy necessary for cell survival. Indeed, excessive or irreversible activation of pannexons leads to cell death [53,63,94,95]. The self-inhibition of pannexons by ATP is a component of fine tuning of a potentially dangerous channel by preventing prolonged opening.…”

Purinergic signaling in Parkinson's disease. Relevance for treatment

“…It is of substantial interest that astrocytic ATP may be also released into the extracellular space as a VT signaling molecule through pannexin channels permeable to ATP and other molecules of less than 1.5kD [42,43]. The pannexin1 channel not only allows ATP efflux along a concentration gradient but is also activated by ATP from the extracellular side via P2Y and P2X receptors, especially P2X 7 receptors [44,45].…”

“…Apoptotic cell death develops due to caspase-mediated events and disappearance of membrane ion gradients [43,49]. It is also suspected that the negative feedback involves in intact striatum Ado tone plays a key role in fine-tuning the motor control exerted by dopamine (see [54] for review).…”