Synaptic Metal Ion Dynamics and Signaling

Background Information:

Transition metal ions (metals) such as copper, iron, and zinc play key roles in many cellular processes. In addition to the clearly established roles as co-factors of enzymes and various other proteins, metals are emerging as major effector of molecular signaling. Our broad research interest is to understand the role of metal ions in neuronal cell biology and signaling. As metal homeostasis is impaired in neurodegenerative and cognitive disorders, our fundamental investigations on metal dynamics and regulation aim to get insights on the aetiology of disease mechanisms.

In general, metals exhibit high binding affinity towards proteins and small molecules, and are considered to be mostly in the ligand-bound state, in contrast to the negligible proportion of free metal ions inside the cell. However, rapid changes in the membrane potential and pH by synaptic activity produce transient changes in the free metal ion concentration in neuronal compartments, which may trigger fast signaling events mediated by metal ions in the neuron. Despite the abundance of metal binding proteins, metal dynamics and signalling is largely unexplored owing to technological limitations. Using recently developed imaging tools including those from our group, we study the interaction between neuronal activity and cell biological processes mediated by metal ions, which is critical to understand why metal homeostasis is disturbed in many neuronal disorders.

Our recent work (Upmanyu et al, 2022, Neuron) revealed a novel role for zinc in synaptic transmission. Using recently developed super resolution microscopy methods such as DyMIN STED and MINSTED, we found that zinc transporter 3 (ZnT3), which is responsible for loading zinc into synaptic vesicles, is one of the most abundant vesicular neurotransmitter transporters in the brain and co-localized on the same vesicles that store glutamate. With the help of novel biochemical assays and electrophysiology, we showed that cytoplasmic zinc regulates vesicular glutamate content and the synaptic quantal size through ZnT3, demonstrating a direct role for zinc in the determination of synaptic strength. Currently, we try to understand the holistic molecular scheme of zinc biology at the synaptic terminal.

In order to build a comprehensive understanding of neuronal metal homeostasis, we employ Minflux super resolution nanoscopy, which delivers 3D multicolor nanometer resolution in cells, to determine the nanoscale organization of endogenous metal transporters on the cell membrane and subcellular organelles in the intact nervous system. By combining the above approach with DNA-PAINT acquisition, we enhance the multiplexing capabilities to achieve realistic in situ structural biology of metal transporters, which is critical to understand and interrogate the local metal dynamics in neurons.


  1. Michael Weber, Henrik von der Emde, Marcel Leutenegger, Philip Gunkel, Volker C. Cordes, Sivakumar Sambandan, Taukeer A. Khan, Jan Keller-Findeisen, Stefan W. Hell. MINSTED nanoscopy enters the Ångström localization range. bioRxiv, 2022, DOI
  2. Neha Upmanyu, Jialin Jin, Henrik von der Emde, Marcelo Ganzella, Leon Bösche, Viveka Nand Malviya, Evi Zhuleku, Antonio Politi, Momchil Ninov, Ivan Silbern, Marcel Leutenegger, Henning Urlaub, Dietmar Riedel, Julia Preobraschenski, Ira Milosevic, Stefan Hell, Reinhard Jahn and Sivakumar Sambandan. Co-localization of different neurotransmitter transporters on the same synaptic vesicle is sparse except for VGLUT1 and ZnT3. Neuron, 2022,  DOI
  3. Robert Luck , Severino Urban, Andromachi Karakatsani , Eva Harde , Sivakumar Sambandan, LaShae Nicholson, Silke Haverkamp, Rebecca Mann, Ana Martin-Villalba, Erin Schuman, Amparo Acker-Palmer, Carmen Ruiz de Almodóvar, VEGF/VEGFR2 signaling regulates hippocampal axon branching during development, Elife, 2019, doi: DOI
  4. Sivakumar Sambandan, Gueney Akbalik, Lisa Kochen, Josefine Kahlstatt, Caspar Glock, Jennifer Rinne, Georgi Tushev, Beatriz Alvarez-Castelao, Alexander Heckel and Erin M. Schuman. Activity-dependent spatially-localized miRNA maturation in neuronal dendrites, Science, 2017, Vol. 355, Issue 6325, p634-637.
  5. Irena Vlatkovic, Sivakumar Sambandan, Georgi Tushev, Mantian Wang, Irina Epstein, Caspar Glock, Nicole Fuerst, Iván Cajigas, Erin M. Schuman. Poly(A) Binding Protein Nuclear 1 regulates the polyadenylation of key synaptic plasticity genes and plays a role in homeostatic plasticity, bioRxiv, 2017, DOI
  6. Christoph Schanzenbächer, Sivakumar Sambandan, Julian Langer, Erin M. Schuman. Nascent proteome remodeling following homeostatic scaling at hippocampal synapses, Neuron, 2016, Vol. 92, Issue 2, p358-37
  7. Hanus C, Geptin H, Tushev G, Garg S, Alvarez-Castelao B, Sambandan S, Kochen L, Hafner AS, Langer JD, Schuman EM. Unconventional secretory processing diversifies neuronal ion channel properties, eLife, 2016, DOI
  8. Gueney Akbalik, Kasper Langeback Jensen, Sivakumar Sambandan, Casper Glock, Georgi Tushev, Erin M. Schuman. Visualization of dendritic newly synthesized RNAs in rat hippocampus, RNA Biology, 2016, Vol. 14, Issue 1, p20–28.
  9. Xintian You, Irena Vlatkovic, Ana Babic, Tristan Will, Irina Epstein, Georgi Tushev, Guney Akbalik, Mantian Wang, Caspar Glock, Xi Wang, Jingyi Hou, Hongyu Liu, Wei Sun, Sivakumar Sambandan, Tao Chen, Erin M. Schuman, Wei Chen. Neural circular RNAs are derived from synaptic genes and regulated by neural development and plasticity, Nature Neuroscience, 2015, Vol. 18, p603–610. 
  10. Sivakumar Sambandan, J.F. Sauer, I. Vida, M. Bartos. Associative plasticity at excitatory synapses facilitates recruitment of fast-spiking interneurons, Journal of Neuroscience, 2010. Vol. 30, Issue 35, p11826-11837
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