Supported by experiments and computational modeling of direct interactions between an agonist or antagonist with this cavity as well as the results from a transgenic mouse harboring a mutation in the cavity to prevent bilirubin binding, we propose a noncanonical paradigm, in which bilirubin is released from endogenous sources during ischemia and potentially serves as a volume neurotransmitter or a specific agonist ligand for TRPM2 to aggravate brain injury in stroke. The gene discussed is TRPM2; the disease is stroke disorder.