Shyam Krishnakumar, PhD
Research & Publications
Biography
Locations
Research Summary
Understanding how information is transmitted reliably with sub-millisecond precision from one nerve cell to another and how alterations in information processing leads to neurological disorders
Specialized Terms: Synaptic Transmission, Synaptic Regulation, Membrane Fusion, Neurological Disorders
Extensive Research Description
Regulation of Synaptic Transmission
The release of neurotransmitters at the neuronal synapses is precisely timed to follow the arrival of a nerve impulse. To achieve this, synaptic vesicles (loaded with neurotransmitters) are already docked in the presynaptic membrane, ready to release the neurotransmitters when the signal arrives. The protein machinery involved in this process are SNARE proteins, which catalyze the fusion of the vesicles; and set of chaperones (Munc18/Munc13) and regulatory proteins (Complexin and Synaptotagmin), which synchronize the release of the neurotransmitter to the triggering signal (calcium ions). Our research is focused on elucidating the molecular architecture at the presynaptic terminals and determine the precise sequence of molecular events that leads to Ca2+-triggered synaptic vesicle fusion.
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 approaches including biochemistry, biophysics, structural biology, cell biology including super-resolution microscopy, electrophysiology, live neuronal imaging, and computational modelling.
Coauthors
Research Interests
Synaptic Transmission; Neurology; Neurosciences
Selected Publications
- Structural basis for the clamping and Ca2+ activation of SNARE-mediated fusion by synaptotagmin.Grushin K, Wang J, Coleman J, Rothman JE, Sindelar CV, Krishnakumar SS. Structural basis for the clamping and Ca2+ activation of SNARE-mediated fusion by synaptotagmin. Nature Communications 2019, 10:2413.
- Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis.Bello OD, Jouannot O, Chaudhuri A, Stroeva E, Coleman J, Volynski KE, Rothman JE, Krishnakumar SS. Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115:E7624-E7631.
- Synergistic control of neurotransmitter release by different members of the synaptotagmin family.Volynski KE, Krishnakumar SS. Synergistic control of neurotransmitter release by different members of the synaptotagmin family. Current Opinion In Neurobiology 2018, 51:154-162.
- Hypothesis - buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission.Rothman JE, Krishnakumar SS, Grushin K, Pincet F. Hypothesis - buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission. FEBS Letters 2017, 591:3459-3480.
- Dilation of fusion pores by crowding of SNARE proteins.Wu Z, Bello OD, Thiyagarajan S, Auclair SM, Vennekate W, Krishnakumar SS, O'Shaughnessy B, Karatekin E. Dilation of fusion pores by crowding of SNARE proteins. ELife 2017, 6.
- Ring-like oligomers of Synaptotagmins and related C2 domain proteins.Zanetti MN, Bello OD, Wang J, Coleman J, Cai Y, Sindelar CV, Rothman JE, Krishnakumar SS. Ring-like oligomers of Synaptotagmins and related C2 domain proteins. ELife 2016, 5.
- Using ApoE Nanolipoprotein Particles To Analyze SNARE-Induced Fusion Pores.Bello OD, Auclair SM, Rothman JE, Krishnakumar SS. Using ApoE Nanolipoprotein Particles To Analyze SNARE-Induced Fusion Pores. Langmuir : The ACS Journal Of Surfaces And Colloids 2016, 32:3015-23.
- Re-visiting the trans insertion model for complexin clamping.Krishnakumar SS, Li F, Coleman J, Schauder CM, Kümmel D, Pincet F, Rothman JE, Reinisch KM. Re-visiting the trans insertion model for complexin clamping. ELife 2015, 4.
- Calcium sensitive ring-like oligomers formed by synaptotagmin.Wang J, Bello O, Auclair SM, Wang J, Coleman J, Pincet F, Krishnakumar SS, Sindelar CV, Rothman JE. Calcium sensitive ring-like oligomers formed by synaptotagmin. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111:13966-71.
- Conformational dynamics of calcium-triggered activation of fusion by synaptotagmin.Krishnakumar SS, Kümmel D, Jones SJ, Radoff DT, Reinisch KM, Rothman JE. Conformational dynamics of calcium-triggered activation of fusion by synaptotagmin. Biophysical Journal 2013, 105:2507-16.
- A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion.Krishnakumar SS, Radoff DT, Kümmel D, Giraudo CG, Li F, Khandan L, Baguley SW, Coleman J, Reinisch KM, Pincet F, Rothman JE. A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion. Nature Structural & Molecular Biology 2011, 18:934-40.
- Complexin cross-links prefusion SNAREs into a zigzag array.Kümmel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG, Pincet F, Rothman JE, Reinisch KM. Complexin cross-links prefusion SNAREs into a zigzag array. Nature Structural & Molecular Biology 2011, 18:927-33.
- Circular oligomerization is an intrinsic property of synaptotagmin.Wang J, Li F, Bello OD, Sindelar CV, Pincet F, Krishnakumar SS, Rothman JE. Circular oligomerization is an intrinsic property of synaptotagmin. ELife 2017, 6.