Title: Downstream regulatory element antagonist modulator and neuronal calcium sensor one as potential targets for neurotoxins, drugs, and pollutants.

By Jaroslava Miksovska, Ph.D.

Associate Professor, Department of Chemistry and Biochemistry, Florida International University

Abstract

Neuronal calcium sensors (NCS), including neuronal calcium sensor 1 (NCS1) and the downstream regulatory element antagonist modulator (DREAM), form a family of EF-hand calcium-binding proteins that regulate diverse physiological and pathological processes. These range from neuronal development, exocytosis, learning, and memory to 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 explored the role of NCS proteins as molecular targets for neurotoxic metals and environmental pollutants. We demonstrated that the EF-hand domains of NCS1 and DREAM can bind non-physiological metal ions—such as Hg²⁺, Pb²⁺, Cd²⁺, and Mn²⁺—with submicromolar affinity. Despite their close structural and sequence similarity, NCS1 and DREAM display distinct metal-binding affinities and conformational responses. We further discovered that both NCS1 and DREAM bind Li⁺ with submillimolar affinity. Lithium binding induces structural alterations and, in DREAM, modulates its interaction with presenilin-binding domains. These findings suggest that DREAM—and potentially other members of the NCS family—may serve as intracellular targets of lithium, offering a possible molecular explanation for lithium’s neuroprotective effects. Additionally, kinetic analyses revealed that neuronal calcium sensors recognize Ca²⁺ through a conformational selection mechanism, indicating that these proteins exist in a dynamic equilibrium between at least two major conformational states. Together, our findings establish neuronal calcium sensors as versatile metal-binding proteins that interact not only with Ca²⁺ but also with neurotoxic and therapeutic metal ions. The distinct structural and functional responses of NCS1 and DREAM to different metals highlight their sensitivity to cellular metal homeostasis and their potential roles in mediating neurotoxicity or neuroprotection.

Short Bio

Dr. Jaroslava Miksovska is an Associate Professor in the Department of Chemistry and Biochemistry at Florida International University. She earned her Ph.D. in Enzymology from the University of Orsay, Paris XI. She has built a distinguished academic career focused on protein structure, enzymatic mechanisms, and molecular interactions. Her research utilizes advanced spectroscopic and thermodynamic tools to elucidate the structural dynamics and thermodynamics of metal–protein and small-molecule interactions. By combining various state-of-the-art spectroscopic and photothermal methods with in silico studies, she seeks to uncover the fundamental mechanisms that govern ligand binding, conformational switching, and metal ion coordination in biologically and environmentally relevant systems. Ultimately, their goal is to translate these molecular-level insights into (1) new therapeutic strategies for neuropsychiatric and toxicological disorders, (2) responsive molecular sensors for metal ions and environmental pollutants, and (3) broadly applicable analytical platforms for probing protein dynamics under near-physiological conditions.

Light refreshments and snacks will be provided from 11:30 AM to noon, followed by the Seminar at 12:00 PM. 

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