Figure 12.
Schematic model of the intercellular signaling mechanisms that underlie the effects of NKA on neuroinflammation in the ENS. NKA and SP released from intrinsic neuronal varicosities drive NK1R activation on enteric neurons and NK2R activation on nociceptive neurons and enteric neurons. Activation of NKRs drives adenosine triphosphate (ATP) release from enteric neurons that recruit activity in surrounding enteric glia by activating P2Y1Rs. Intracellular signaling pathways downstream of P2Y1R activation drive glial Ca2+ responses that contribute to Cx43 hemichannel opening and ATP release that further enhances glial responses, drives P2X7R-mediated neuroinflammation, and P2Y1R activation on nociceptive neurons. ADP, adenosine diphosphate. eNTPdase, ectonucleoside triphosphate diphosphohydrolase 2.