Yet, this adaptive strategy carries risk since tonic VGCC activity plays a synergistic role with the P2X7 receptor/channels activated in stage 4 to accelerate the hyperosmotic-induced death of the conjunctival goblet cells whose loss is a histopathological feature of irreversible mucin-deficient dry eye. This evidence concerns the gene MUC5AC and Keratoconjunctivitis sicca.