Neurobiological and Chemical Characterization of the Cyanobacterial Metabolite Veraguamide E.

Ver E's structure was validated by (1)H NMR, HRMS, and molecular networking analyses. Computational docking and NMR titration confirmed direct, saturable, and tight binding of Ver E to the human Sigma-2 receptor/transmembrane protein 97 (σ(2)R/TMEM97). Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca(2+) levels without modulating store-operated calcium entry (SOCE). Multi-well microelectrode array experiments using human induced pluripotent stem cell (hiPSC) derived nociceptors showed that Ver E significantly reduced neuronal activity at physiological temperatures, but not under heat-stress conditions. Ver E exhibited no cytotoxicity at concentrations up to 30 μM in HEK293 cells, and immunocytochemistry confirmed that it does not alter phosphorylated eIF2α (p-eIF2α) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a non-toxic compound capable of selectively modulating neuronal excitability, thereby advancing the development of novel therapeutics for pain management.