The P2X7 receptor–pannexin-1 complex decreases muscarinic acetylcholine receptor–mediated seizure susceptibility in mice
Ji-Eun Kim, Tae-Cheon Kang
Ji-Eun Kim, Tae-Cheon Kang
Published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):2037-2047. https://doi.org/10.1172/JCI44818.
View: Text | PDF
Research Article Neuroscience

The P2X7 receptor–pannexin-1 complex decreases muscarinic acetylcholine receptor–mediated seizure susceptibility in mice

Abstract

Pannexin-1 (Panx1) plays a role in the release of ATP and glutamate in neurons and astrocytes. Panx1 can be opened at the resting membrane potential by extracellular ATP via the P2X7 receptor (P2X7R). Panx1 opening has been shown to induce neuronal death and aberrant firing, but its role in neuronal activity has not been established. Here, we report the role of the P2X7R-Panx1 complex in regulating muscarinic acetylcholine 1 (M1) receptor function. P2X7R knockout (P2X7–/–) mice showed greater susceptibility to seizures induced by pilocarpine (PILO), an M1 receptor agonist, than their WT littermates, despite having similar levels of hippocampal M1 receptor expression. This hypersensitivity to PILO in the P2X7–/– mice did not involve the GABA or glutamate system. Both administration of P2X7R antagonists and gene silencing of P2X7R or Panx1 in WT mice increased PILO-induced seizure susceptibility in a process mediated by PKC via intracellular Ca2+ release. Therefore, we suggest that the P2X7R-Panx1 complex may play an important role as a negative modulator of M1 receptor–mediated seizure activity in vivo.

Authors

Ji-Eun Kim, Tae-Cheon Kang

×

Figure 9

Hypothesized role of the P2X7R-Panx1 complex in regulating M1 receptor activity.

Options: View larger image (or click on image) Download as PowerPoint
Hypothesized role of the P2X7R-Panx1 complex in regulating M1 receptor a...
(A) In WT mice, M1 receptor activation triggers IP3 production and increases ICR (i–iii). Elevated intracellular Ca2+ contributes to opening Panx1 (iv), which allows IP3 clearance, Ca2+ wave propagation, and ATP release (v). Releasing ATP through Panx1 activates P2X7R (vi), which desensitizes the M1 receptor and sustains Panx1 opening for clearance of IP3 (vii and viii). In turn, PKC activation leads to closure of P2X7R and Panx1 (ix). (B) In P2X7–/– mice, M1 receptor activation triggers ICR via IP3 production (i–iii). Elevated intracellular Ca2+ contributes to opening Panx1 (iv). In the absence of P2X7R, Panx1 opening and M1 receptor desensitization cannot be sustained (v). Simultaneously, PKC activation rapidly closes the Panx1 channel (vi), which induces accumulation of intracellular IP3 caused by failure of IP3 clearance and prolonged M1 receptor activation (vii). See Discussion for details.