Proposed mechanism by which cationic neurotoxicants disrupt ATP-induced calcium signaling in astrocytes.

This scheme represents a novel pathophysiologic mechanism that calcium signaling in astrocytes is an important target of selected dopaminergic neurotoxicants. Adenosine triphosphate (ATP) at nanomolar to micromolar concentrations activates metabotropic purinergic receptors (P2Y), causing phospholipase C (PLC)-dependent release of inositol triphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP₂). IP₃ stimulates release of Ca²⁺ from the endoplasmic reticulum, represented by the initial peak in the trace (blue) and DAG activates TRPC channels, allowing influx of cations, including Ca²⁺, from the extracellular space, represented by the sustained phase of the trace (red). In the presence of MPP⁺ or 6-OHDA, Ca²⁺ influx is disrupted following stimulation with ATP or OAG, thereby diminishing the net movement of Ca²⁺ into the cell.