BPS2026 – Shedding light on the dark channel via large-scale ion channel classification

Ion channels are pore-forming membrane proteins that control the flow of ions across cellular membranes, enabling processes such as electrical signaling, sensory perception, and maintenance of cellular homeostasis. Because they are central to physiology and implicated in numerous diseases, ion channels represent one of the largest and most important classes of drug targets. Among them, calcium homeostasis modulator (CALHM) channels are poorly understood voltage-gated ion channels implicated in neuronal signaling, taste perception, and neurological disease, yet their molecular mechanisms and evolutionary diversity remain largely unexplored. Ion channel genes in the human genome are essential for cellular function and disease, comprising one of the largest classes of druggable proteins, yet limited understanding of their diverse roles hampers development of selective chemical probes. Vast ion channel sequence data across organisms offer untapped potential to reveal unique regulatory mechanisms and functional specializations, but extensive sequence diversification and the lack of a unified resource make these data difficult to use effectively. Here, we integrate sequence, structural, and functional data on 419 human ion channels from disparate sources, combining large language model-assisted literature mining to curate a comprehensive “channelome,” and use orthology inference to expand ion channel identification to over 48,000 orthologs across diverse taxa. We show that conservation depth and taxonomic distribution can be translated into functional similarity by clustering ion channels into functionally relevant groups, enabling predictions for understudied members. As proof of concept, we identify co-conserved sequence patterns in the CALHM family and demonstrate, through mutational and electrophysiological analyses, that evolutionarily constrained residues altered in human disease significantly affect channel gating. This work provides new tools and resources for large-scale comparative ion channel analysis, laying the groundwork for functional characterization of “dark” channels and advancing therapeutic discovery.