Downstream Regulatory Element Antagonist Modulator and Neuronal Calcium Sensor One As Potential Targets for Neurotoxins, Drugs, and Pollutants

Neuronal calcium sensors (NCS), including neuronal calcium sensor 1 (NCS1) and downstream regulatory element antagonist modulator (DREAM), constitute a family of calcium-binding proteins involved in a wide range of physiological and pathological processes. These include neuronal development, exocytosis, learning and memory, pain perception, and the progression of disorders such as Alzheimer’s and Parkinson’s diseases, autism, and cancer.

Over the past eight years, our research has focused on the role of NCS proteins as molecular targets for neurotoxic metals, pharmaceutical compounds, and environmental pollutants. We have shown that the EF-hand calcium-binding domains in NCS1 and DREAM can also bind non-physiological metal ions, including Hg²⁺, Pb²⁺, Cd²⁺, and Mn²⁺, with sub-micromolar affinity. Despite high structural and sequence similarity, these proteins exhibit distinct metal-binding affinities and structural responses, influencing their quaternary, tertiary, and secondary structures and their interactions with peptides that mimic intracellular effector proteins.

We also found that NCS1 and DREAM bind Li⁺ with sub-millimolar affinity. Lithium binding changes their structural properties, and in the case of DREAM, it influences how they interact with presenilin-binding sites. These results suggest that DREAM—and possibly other NCS family members—may serve as intracellular targets of lithium, providing a molecular explanation for its neuroprotective effects.

Furthermore, we have demonstrated that both NCS1 and DREAM interact with the anticancer drugs doxorubicin and paclitaxel. These drug-protein associations disrupt critical protein-peptide interactions, including those between NCS1 and D2R, and DREAM with site-1, site-2, and helix-9 peptides. Such interactions may underlie mechanisms of drug-induced neurotoxicity.

Our findings highlight the molecular versatility of neuronal calcium sensors and their potential roles as targets for therapeutic agents and environmental toxins.