Fig. 3

In cells experiencing inflammation, glutamate release into the extracellular space is increased, and Ca²⁺ signaling in cellular networks is over-activated. Several receptors are influenced by the increased expression of TLR4, and the responses of other receptors such as P2 and mGluR5 are also changed. The Na⁺/K⁺-ATPase is downregulated, the glutamate transporters GLT-1 and GLAST are changed, and actin filaments (white bands disorganized) in the cytoskeleton are reorganized, thereby abolishing the balance between the Ca²⁺ regulatory processes. This process leads to the down-regulation of intercellular Ca²⁺ signaling and thereby of Cx43 in gap junctions. ATP is released from the cells and binds to P2 purinoceptors, which generates extracellular Ca²⁺ oscillations/waves and increased release from internal stores. The increased release of pro-inflammatory cytokines such as IL-1β occurs extracellularly. The clearing of increased glutamate concentrations from the extracellular space, which plays a critical role in preventing glutamate excitotoxicity, is attenuated. The illustration was created by Pontus Andersson, ArtProduction, Gothenburg, Sweden