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Dr Sriharsha Kantamneni

PositionLecturer in Therapeutics
LocationNorcroft building, 2.12
DepartmentSchool of Pharmacy and Medical Sciences
Telephone+44 (0) 1274 236072
EmailS.Kantamneni@bradford.ac.uk
Twitter@Harsha_Kantamne
LinkedInVisit my LinkedIn profile
ORCID0000-0002-3750-9447

Research Interests (key words only)

Neuronal membrane proteins, receptor trafficking and degradation, protein-protein interactions, Glutamate / GABA receptors, post-translational modification and ESCRT biology.

Teaching and Supervisory Responsibilities

MPharm

Module leader: Foundation Studies in Pharmacy 1 – Molecules to Structure

Unit lead:

  • Foundation Studies 1, Unit 2 and 3 – Cell and Pathogens
  • Foundation Studies 1, Unit 6 – Receptors and function

Unit team member:

  • Senses Thoughts and Movement 1, Units 5 and 6 – Musculoskeletal problems
  • Nutrition, Metabolism and Reproduction 3, Units 3 and 4 – Gastrointestinal problems
  • Student Selected Component: t-strand (Research topics) 

Student Selected Component:

  • t-strand (Research topics)
  • S-strand (Systematic reviews)

Capability in Pharmacy years 1, 2, 3 and 4

Personal Academic Tutor for 18 students

Clinical Sciences

  • Integrated Medical Sciences (1st year)
  • Central Nervous System Mechanisms, Disorders and Therapeutics (3rd year)

Administrative Responsibilities

  • MPharm Admission Tutor and On-campus events lead
  • UK-China Neuroprotection Research Platform Coordinator

Study History

  • Pharmacy, Bachelors, DR. MGR Medical University, India - 1998
  • MSc Pharmacology and Biotechnology, Sheffield Hallam University, UK - 2000
  • PhD Molecular and Cellular Neuroscience, University of Bristol, UK - 2004
  • APD in Management Studies (level7), City of Bristol College, UK - 2006
  • PGCHEP (postgraduate certificate in higher education practice) (Sep 2013 – July 2015)
    University of Bradford, Bradford, UK

Professional History

2011- June 2013: Research Fellow, Dept of Genetics, Research centre, King Faisal Specialist Hospital, Riyadh, Saudi Arabia

2005 - 2010: Research Associate, MRC Centre for Synaptic Plasticity, University of Bristol, Bristol, UK

Professional Activities

  • Member of International Society for Neurochemistry
  • Member of British Neuroscience Association
  • Member of British Pharmacological Society
  • Member of Biochemical Society
  • Member of British Society for Cell Biology

Research Areas

The SOCS3/TBK1 interface

Development of novel therapeutics to prevent MND and neurodegeneration: Sporadic motor neuron disease (MND) accounts for around 90% of cases with the remaining 10% being inherited. However the mechanisms causing disease are often indistinguishable, suggesting that functional analysis of genes linked with inherited MND can identify mechanisms underlying sporadic cases.

Studies in multiple patient cohorts have shown that inactivating mutations in the TBK1 (TANK binding kinase 1) gene cause both inherited and sporadic MND & frontotemporal dementia. TBK1 interacts with and phosphorylates optineurin and p62, promotes mitophagy and is part of a common pathway known to regulate autophagy and neurodegeneration. SOCS3 (suppressor of cytokine signalling 3) is an inducible protein that binds and regulates the ubiquitination and degradation of specific substrates, including TBK1.

As SOCS3 down-regulates TBK1 expression, we hypothesise that disruption of the SOCS3-TBK1 interface in neurons can rescue TBK1 function by decreasing its degradation and thus represents a tractable new target for therapeutic intervention to limit neurodegeneration in MND. ESCRT proteins as therapeutic targets in Alzheimer's disease: Protein degradation is of fundamental importance for neuronal function and perturbation of degradative pathways has been implicated in multiple neurodegenerative disorders but particularly Alzheimer's disease (AD). ESCRT proteins mediate trafficking of membrane proteins to lysosomes and their degradation. ESCRT consists of four multiprotein complexes (ESCRT–0, –I, –II and –III) that mediate endocytosis of cell surface proteins including glutamate receptors (Kantamneni et al., 2009) through multivesicular bodies (MVBs) to lysosomes for degradation.

Previously, ESCRT-III subunit CHMP2B immunopositivity has been identified in granulovacuolar degeneration bodies in neurons of AD hippocampus. One of the key feature of early onset AD models is the intracellular amyloid-β (Aβ) accumulation that precedes the appearance of Aβ in extracellular plaques. Recently it has been shown that Aβ is generated through proteolytic processing of amyloid precursor protein (APP), which is localised to MVBs and that it is delivered to lysosomes for degradation. Transient depletion of either ESCRT-0 or -I components, inhibited targeting of APP to MVBs and the subsequent delivery to lysosomes. This resulted in increased intracellular Aβ accumulation, accompanied by dramatically decreased Aβ secretion.

In summary, ESCRT machinery has multiple roles in limiting intracellular Aβ accumulation through targeting of APP to the lysosomes for degradation as well as trafficking & degradation of neurotransmitters receptors. Based on these observations, my lab is testing the hypothesis that, since in AD models ESCRTs function is abnormal, studying ESCRT mechanisms and its regulation in neurons has the potential to identify new molecular targets for therapeutic intervention in AD. Mechanisms regulating NMDA-mediated down-regulation of neuronal GABAB receptors in ischemia: GABAB receptors are heterodimers of GABAB1 and GABAB2 subunits and require both subunits for functional signalling. Previously I have shown that exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) ischemic model, increases GABAB1 but decreases GABAB2 surface expression in neurons. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDA receptor-selective antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is a critical regulator of GABABR trafficking and function to regulate neuronal responsiveness and survival. Building on this work, I hypothesize that the loss of NMDA receptor-mediated inhibition represent a novel mechanism by which excititoxicity triggers death of damaged neurons.

Current Projects

  • May 2017; Alzheimer’s Research Trust Network (PI): The SOCS3/TBK1 interface: An opportunity for development of novel therapeutics to prevent MND and neurodegeneration

  • March 2016; Alzheimer’s Research UK - Yorkshire regional network (PI): ESCRT proteins as therapeutic targets in Alzheimer's disease

  • March 2016; Royal Society (PI): Mechanisms regulating NMDA-mediated down-regulation of neuronal GABAB receptors in ischemia

  • Feb 2016; Alzheimer’s Research UK (Co-PI): Real-time imaging of molecular mechanisms underlying synaptic dysfunction and neurodegeneration in Alzheimer’s disease

Publications

  • Chapter: Modulation of Neurotransmission by the GABAB Receptor (2016) Sriharsha Kantamneni Book Name: GABAB Receptor, pp 109-128 Volume 29 of the series The Receptors DOI 10.1007/978-3-319-46044-4_7
  • Sriharsha Kantamneni (2015) Cross-talk and regulation between glutamate and GABAB receptors. Front Cell Neurosci. 9:135. doi: 10.3389/fncel.2015.00135
  • Sriharsha Kantamneni*, Immaculada M. Gonzàlez-Gonzàlez, Helena I Cimarosti, Jia Luo, Nadia Jaafari and Jeremy M Henley* (2014). Differential regulation of GABAB receptor trafficking by different modes of NMDA receptor signaling. J Biol Chem. 289(10): 6681–6694. (*co-corresponding author)
  • Nadia Jaafari, Filip Konopacki, Thomas F. Owen, Sriharsha Kantamneni, Philip Rubin, Tim J. Craig, Kevin A. Wilkinson and Jeremy M. Henley (2013). USUMOylation is required for glycine-induced increases in AMPA receptor surface expression (ChemLTP) in hippocampal neuronsU. PLoS ONE. 8(1):e52345
  • Sophie E L Chamberlain, Inmaculada M González-González, Kevin A Wilkinson, Filip A Konopacki, Sriharsha Kantamneni, Jeremy M Henley & Jack R Mellor (2012). SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity Nature Neuroscience. 15(6):845-52
  • Sriharsha Kantamneni, Kevin A. Wilkinson, Nadia Jaafari, Emi Ashikaga, Daniel Rocca, Philip P. Rubin, Susan C. Jacobs, Atsushi Nishimune and Jeremy M. Henley. (2011) Activity-dependent SUMOylation of the brain-specific scaffolding protein GISP. Biochem Biophys Res Commun. 409(4):657-62
  • Filip Konopacki, Nadia Jaafari, Dan L. Rocca, Kevin A. Wilkinson, Sophie Chamberlain, Philip Rubin, Sriharsha Kantamneni, Jack R. Mellor and Jeremy M. Henley (2011). Agonist-induced PKC phosphorylation regulates GluK2 SUMOylation and kainate receptor endocytosis. Proc Natl Acad Sci USA. 108(49):19772-7
  • Laura Ceolin, Sriharsha Kantamneni, Gareth R. Barker, Lydia Hanna, Lynnette Murray, Elizabeth C. Warburton, Emma S. Robinson, James A. Monn, Stephen M. Fitzjohn, Graham L. Collingridge, Zuner A. Bortolotto and David Lodge. (2011) Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype. J Neuroscience. 31(18):6721-31
  • Sriharsha Kantamneni, Kevin A. Wilkinson and Jeremy M. Henley. (2011) Ubiquitin regulation of neuronal excitability. Nature Neuroscience. 14(2):126-8
  • Sriharsha Kantamneni, David Holman*, Kevin A. Wilkinson*, Atsushi Nishimune and Jeremy M. Henley. (2009) UGISP increases neurotransmitter receptor stability by down-regulating ESCRT-mediated lysosomal degradation. Neuroscience Letters. 452(2): 106-10
  • Helena Cimarosti*, Sriharsha Kantamneni* and Jeremy M. Henley. (2009) Changes in GABAB receptors following ischemic challenges in organotypic cultures. Neuropharmacology. 56(8): 1088-96. (*Equal contribution)
  • Sriharsha Kantamneni*, David Holman*, Kevin A. Wilkinson, Sônia A.L. Corrêa, Marco Feligioni, Simon Ogden, William Fraser, Atsushi Nishimune and Jeremy M. Henley. (2008) GISP binding to TSG101 increases GABAB2 receptor stability by down-regulating ESCRT-mediated lysosomal degradation. J. Neurochemistry. 107(1): 86-95. (*Equal contribution)
  • Sriharsha Kantamneni, Sônia A.L. Corrêa, Gina K. Hodgkinson, Guido Meyer, Ngoc Nga Vinh, Jeremy M. Henley and Atsushi Nishimune. (2007). UGISP: A novel brain specific protein that promotes surface expression and function of GABAB receptors. J. Neurochemistry 100(4); 1003-17

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