Connexin and Pannexin Hemichannels: Broad-Spectrum Players in Neuroinflammatory Signaling

Connexin- and pannexin-formed hemichannels have emerged as pivotal, upstream amplifiers of neuroinflammation. Under physiological stressors-depolarization, Ca²⁺ overload, redox shift, or cytokine exposure-these large pores release adenosine triphosphate, glutamate, and other danger signals that activate P2X/P2Y and N-methyl-D-aspartate receptors, ignite NLR family pyrin domain containing (NLRP) 3 inflammasome, and propagate Ca²⁺/reactive oxygen species waves between mast cells, microglia, astrocytes, oligodendrocytes, neurons, and brain endothelium. Evidence across acute (e.g., stroke, trauma, seizure, and sepsis) and chronic (e.g., Alzheimer's, and multiple sclerosis) models shows that genetic ablation or pharmacological blockade of hemichannels shrinks lesions, preserves synaptic plasticity, restores blood-brain barrier integrity, and rescues cognition, often without altering the primary pathogenic trigger. Translational leads include mimetic peptides (e.g., Gap19, ¹⁰panx1), the nanomolar, gap junction-sparing small-molecule D4, and the pleiotropic alkaloid boldine, all of which curb epileptiform activity, neurodegeneration, and depressive-like behavior. Yet key gaps persist, such as the long-term safety of chronic inhibition, which remains poorly defined and will be critical to translate these "gatekeeper" channels into next-generation neuro-anti-inflammatory therapeutics.