Synaptic Metal ion Dynamics and Signalling
Mobility and stability of proteins and ligands in space determine initiation of cellular signalling. Transition metal ions such as zinc and copper act as ligands and regulate many fundamental biological processes by binding to proteins and their function. Indeed, more than 20% of human genome encodes metal binding proteins, which includes signaling proteins, enzymes, and large fraction of factors that regulate gene expression, potentially rendering metals as a master regulator of cellular processes. To understand the function of metal ions as a signalling entity, it is crucial to understand spatial dynamics of labile metal ions and its regulation in cellular microenvironment. Albeit severe technological challenges to study metals ions, latest advances in the field of metallochemistry resulted in the development of an array of new tools such as sensors, probes, including genetically encoded fluorescent indicators, to monitor metal ion dynamics with high sensitivity and specificity, opening up possibilities to investigate the vast potential of metal ion signalling in cellular function and dysfunction.
Why is metal ion signalling important in the study of brain?
Metal ion dishomeostasis is prevalently exhibited in both neurodegenerative and psychiatric diseases in humans suggesting crucial role for metal ions in normal function of neuronal cell biological processes. Furthermore, several key synaptic proteins (e.g. NR1, Shank3) whose mutations are implicated in prominent neurological disorders are metal binding proteins suggesting that disruption of local metal environment may be involved in the aetiology of many neurological conditions. Interestingly, latest synaptic proteomics data reveal presence of abundant synaptic metal binding proteins suggesting significant role of metal ion signalling in synapse function and dysfunction. However, the role of metals ions in synapse physiology and pathology is poorly understood and warrants renewed efforts with an interdisciplinary approach to delineate the chemistry in synaptic biology.
We work on the hypothesis that transition metal ions act as mobile signals and can serve as dynamic regulators of synapse function and local cell biological mechanisms owing to the presence of abundant protein sensors, with binding affinities comparable to physiological local metal ion concentration.
The broad research interest is to investigate the role of metal ions in information processing in neurons. Does neuronal synaptic and action- potentials affect cellular metal homeostasis and how does it contribute to cellular and synaptic signalling? What are the synaptic proteins that are functionally regulated by local metal ion dynamics and how does it affect synaptic molecular logic and local computing? These broad questions are addressed in individual projects focusing on specific metal ions and proteins.
Our recent work revealed generation of miRNA and inhibition of local protein synthesis in single spines following synaptic activation suggesting complete outsourcing of complex cell biological mechanisms to distant synapses from the neuronal cell body. We are particularly interested in how these local cell biological mechanisms are affected by metal ion dynamics and how it is regulated by synaptic activity and plasticity. To address various questions, we use advanced live-cell imaging, electrophysiology and biochemical approaches in brain tissues and neuronal cultures.
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