Calcium signaling is a robust, tightly regulated pathway which mediates every vital cellular function through the propagation of localized calcium flux. Transient receptor potential vanilloid type 2 (TRPV2) ion channels are calcium-permeable, tetrameric ion channels with implications in several cellular processes such as immune response, neuronal development, and multiple cancers. Despite the impact of TRPV2 on varying physiologies, there is still much to be resolved about the ion channel. One key aspect of understanding the channel’s function is to establish a structural basis for TRPV2 pharmacological channel opening. To investigate the functional mechanism for TRPV2 channel opening, cryogenic-electron microscopy (cryoEM) was used to determine the structures of TRPV2 upon pharmacological activation. Using this cutting-edge structural technique, we were able to elucidate high resolution structures of TRPV2 bound to the pharmacological activators 2-APB and CBD, where we found key residues for drug binding around the flexible S4-S5 linker region. A conserved mechanism for channel opening was also established. In addition to channel opening mechanisms, another vital aspect in channel function is to identify TRPV2’s protein effectors and impacted signaling pathways. To achieve this, we sought to identify TRPV2’s dynamic proximal interactome by employing the catalytically active peroxidase, APEX, to tag proteins proximal to TRPV2. By comparing the protein networks found in the unstimulated state to the pharmacologically activated states of TRPV2, we identified several protein effectors, including the calcium signaling molecules calmodulin and protein kinase C-. Novel functional links between TRPV2 calcium flux and the cell adhesion molecules neural cell adhesion molecule (NCAM) and L1 cell adhesion molecule were established in a neuronal context. Combined, we determined a structural basis for TRPV2 channel opening and established known calcium signaling and novel effector cell adhesion molecules from TRPV2’s dynamic proximity proteome. These studies lay the groundwork for rational drug design and for future cellular studies connecting TRPV2 to cell adhesion.