Shyam Krishnakumar, PhD
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Titles
Assistant Professor
Biography
Shyam S. Krishnakumar, PhD is an Assistant Professor at the Department of Neurology & Nanobiology Institute. Dr. Krishnakumar received his M.S in Biotechnology from the Indian Institute of Technology, Bombay, and his Ph.D. in Biochemistry and Structural Biology from Stony Brook University, NY. In his doctoral research, he made several key discoveries describing how the structure and function of transmembrane proteins are defined by the composition of the membrane-spanning domains. Dr. Krishnakumar did his postdoctoral research on the molecular regulation of synaptic vesicle fusion under the guidance of James E. Rothman (Nobel Prize in Physiology or Medicine, 2013) in the Department of Cell Biology, Yale University School of Medicine (Krishnakumar et al. Nat. Struct. Mol. Biol. 2011; eLife 2015). Subsequently, as a Senior Research Scientist, he directed research focused on dissecting the molecular organization of the vesicle release sites in presynaptic terminals (Volynski and Krishnakumar, Curr. Opin. Neurobiol 2018)
In his own lab, Dr. Krishnakumar aims to delineate the molecular mechanisms of synchronicity and use-dependent plasticity of neurotransmitter release and how it is altered in paroxysmal movement disorders. The balance between different modes of neurotransmitter release and short-term plasticity plays an important role in coordinating activity within neuronal networks and provides a basis for synaptic computation. Any alterations that affect the timing or probability of release result in a wide range of neurological disorders. To this end, he employs multidisciplinary biochemical, biophysical, and structural methods, with a specific focus on systematic biochemical reconstitution strategies.
As part of the Yale-UCL collaborative, Dr. Krishnakumar also has a visiting appointment (Honorary Associate Professor) at the Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London. At UCL, he is pursuing a collaborative research program aimed at understanding the pathophysiology of SNARE-associated neurodevelopmental and movement disorders in molecular terms.
Appointments
Education & Training
- PhD
- Stony Brook University (2007)
- MSc
- Indian Inst Of Tech (2001)
Research
Overview
The release of neurotransmitters at the neuronal synapses is tightly controlled by changes in the presynaptic calcium concentration. To achieve this, synaptic vesicles (loaded with neurotransmitters) are already docked in the presynaptic membrane, ready to release the neurotransmitters when the signal (calcium ion) arrives. The protein machinery involved in this process are SNARE proteins, which catalyze the fusion of the vesicles; calcium sensors that synchronize the release of the neurotransmitter to the triggering calcium signal (Synaptotagmin isoforms) and regulatory proteins (Munc18/Munc13/Complexin ) that are involved in the organization of the release site. Our research is focused on elucidating how vesicular release protein machinery decodes the calcium signals and translate them into complex patterns of neurotransmitter release required for brain function.
The controlled release of neurotransmitters is central to information processing in the nervous system and is altered in many psychiatric and neurological disorders as is clear from well-established clinical benefits achieved by drugs that modulate neurotransmitter biochemistry and/or availability. So, we also aim to uncover the molecular and mechanistic basis for neurological disorders.
Our strategy is based on the systematic quantitative analysis of mutations both novel structure-based designer mutants as well as ‘experiments of nature’ - mutations associated with neurological disorders. We employ multidisciplinary biochemical, biophysical, and structural methods (with a specific focus on systematic biochemical reconstitution strategies) along with electrophysiology and high-resolution imaging in cultured neurons (in collaboration with Prof. Kirill Volynski, UCL Queen Square Institue of Neurology)