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Selvanayagam Nirthanan
MBBS, PhD.
Principal Investigator and Head
Neuropharmacology and Lead Discovery Laboratory
National Neuroscience Institute
11 Jalan Tan Tock Seng, Singapore 308433
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(65) 6357 7515 (Office) |
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(65) 6357 7525 (Lab) |
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(65) 6256 9178 | Email: nirthanan_selvanayagam@nni.com.sg
ADJUNCT APPOINTMENTS AND AFFILIATIONSAssistant Professor (Adjunct), Department of Pharmacology
Yong Loo Lin School of Medicine, National University of Singapore
MD2, 18 Medical Drive, Singapore 119260
Tel: (65) 6516 3264, (65) 6516 3265
Fax: (65) 6773 0579
Assistant Professor (Adjunct), Division of Chemical Biology and Biotechnology
School of Biological Sciences
Nanyang Technological University
60 Nanyang Drive, Singapore 637551
Tel: (65) 6316 2800
Fax: (65) 6791 3856
Visiting Scientist, Cohen Neurobiology Laboratory
Department of Neurobiology, Harvard Medical School
220 Longwood Avenue, Boston, MA 02115, USA
Tel: (1) 617 432 1729
Fax: (1) 617 734 7557
RESEARCH INTERESTS
- Neurobiology of nicotinic acetylcholine receptors.
- Role of neuronal nicotinic acetylcholine receptors in Alzheimer's disease.
- Mammalian endogenous snake toxin-like modulators of nicotinic receptors.
- Pharmacology of ion channel neurotoxins.
- Therapeutic lead molecules from animal venoms and other natural compounds.
- Mechanism of action of general anesthetic drugs with ligand-gated ion channels.
EDUCATION AND TRAINING
- Postdoctoral Fellowship (Neurobiology)
Harvard Medical School, Boston, MA. USA (2002 - 2005).
- PhD (Pharmacology and Biochemistry)
National University of Singapore School of Medicine (2002).
- MBBS (Distinction in Pharmacology)
North Colombo Medical College, Sri Lanka (1994).
HONORS AND AWARDS
- Joseph Brooks Fellowship in Neurobiology
Harvard Medical School, Boston, MA., USA (2002 - 2005).
- Chua Toh Hua Gold Medal for the Most Outstanding PhD Thesis
National University of Singapore, Singapore (2003).
- International Society of Toxinology Award
XIII World Congress on Toxinology, Paris (2000).
- Graduate Research Scholarship
National University of Singapore, Singapore (1999 - 2002).
- Japan International Cooperation Agency Research Fellowship
University of Kumamoto, Japan (1998).
- Wilfred S. E. Perera Gold Medal (Medicine)
North Colombo Medical College, Sri Lanka (1994).
RESEARCH EXPERTISE
- In vitro and in vivo pharmacology (isolated tissue and in vivo animal studies).
- Biochemical pharmacology (radio-isotope binding assays; photoaffinity labelling).
- Two-electrode voltage clamp electrophysiology.
- Protein chemistry (protein purification, mass spectrometry, protein sequencing).
- Bioinformatics (sequence and structural analysis / annotation; molecular modelling).
- Animal behavioural pharmacology.
- Basic molecular biology techniques.
RESEARCH PROFILE
Nicotinic cholinergic signaling in the central and peripheral nervous systemsThe nicotinic acetylcholine receptor (nAChR) is a neurotransmitter receptor that is fundamental for the transfer of information between nerve cells or between nerve and muscle. The muscle type of these receptors is the site of action of the muscle-relaxant drugs used in anesthesia as well as being the target of neurotoxins from snake and cone-snail venoms. In addition, muscle nicotinic receptors are destroyed in the autoimmune disease, myasthenia gravis, leading to progressive muscle weakness. The neuronal subtypes of nAChRs are widely distributed throughout the brain where nicotinic cholinergic signaling plays a key regulatory role to modulate a number of neuronal processes including sensory processing, motor activity, cognitive function and analgesia. Perturbation of cholinergic neurotransmission can result in a variety of neurodegenerative, neuropsychiatric and neurological disorders including Alzheimer's disease, Parkinson's disease, schizophrenia, autosomal dominant nocturnal frontal lobe epilepsy, Tourette's syndrome and depression. The manipulation of cholinergic pharmacology by targeting specific neuronal nAChRs can provide therapeutic intervention in these conditions. Such clinical potential for nAChR-based therapies is providing the basis for the aggressive search and design of selective ligands as drug leads or tools to identify receptor dysfunction in specific pathologies.
Neuronal nicotinic acetylcholine receptors in Alzheimer's diseaseA cholinergic deficit attributed to dysfunction or loss of neuronal nAChRs has clearly been established in Alzheimer's disease. This forms the basis for the current treatment strategy of Alzheimer's disease directed towards the prevention of acetylcholine hydrolysis by inhibition of acetylcholinesterase in an effort to conserve cholinergic function, a therapeutic approach that is limited in efficacy and tolerability. Emerging evidence suggests that β-amyloid, the primary component of the pathognomic amyloid plaques in Alzheimer's disease brains, may interact directly with neuronal α7 and α4β2 nAChRs to mediate amyloid neurotoxicity and have clinically significant downstream effects. Experimental evidence has also implicated α4β2 and α7 nAChR-selective pharmacology in the improvement of several clinical end-points relevant to Alzheimer's disease. Therefore, targeting neuronal nAChRs with highly selective ligands is a scientifically valid point of intervention for the treatment of Alzheimer's disease, which is of obvious clinical significance.
Therapeutic lead discovery from animal venomsThe hetero-oligomeric nature of the nAChRs, together with differential expression of 17 subunits throughout the central and peripheral nervous system, contributes a great diversity of functional and pharmacological receptor properties. Animal venoms are complex mixtures of hundreds of peptide and alkaloid molecules that have evolved to target various physiological processes with exquisite specificity and high potency by binding to receptors and ion channels. Despite their lethal intent, these toxins can be manipulated by chemical and biotechnological means to exploit their potentially useful bioactivity to be applied as therapeutic leads for the development of clinically useful drugs as well as effective diagnostic tools in medicine or scientific probes for studying the biology of their molecular targets. Conus peptides from marine cone snails, in particular, provide a degree of specificity for nicotinic receptors that is far superior to most other known ligands and have already proven to be valuable tools to characterize some subtypes of neuronal receptor subtypes.
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Mammalian Lynx 1
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Snake toxin - Candoxin |
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Amino acid residues in candoxin, a novel neurotoxin from the Malayan krait Bungarus candidus that interact with muscle (left) or neuronal α7 (right) subtypes of the nicotinic acetylcholine receptor. Journal of Biological Chemistry (2002). |
Comparison of the three-fingered protein folds of the mammalian endogenous protein Lynx1 that modulates the function of neuronal nicotinic receptors (Miwa et al, 1999) and the snake neurotoxin Candoxin(Nirthanan et al, 2002). |
Mammalian endogenous snake toxin-like modulators of nicotinic receptorsNon-conventional three finger toxins are a new class of snake toxins with the characteristic "three-finger" protein scaffold, but a cysteine motif distinct from classical α-neurotoxins that act on nAChRs. Their biological activities are largely unknown but available data suggests that nAChR subtypes, including α7 and α1β1γδ, are likely molecular targets. This characteristic "three-finger" protein structural scaffold has also been found to be adopted by endogenous mammalian proteins that are novel modulators of neuronal α7 and α4β2 and possibly other subtypes of nAChRs, raising the intriguing possibility that they are evolutionarily-related, endogenous, structural and functional homologues of snake toxins. Studies of these two diverse classes of structurally similar proteins are expected to yield valuable insight into modulation of cholinergic signaling by mammalian endogenous proteins as well as possible biological targets of novel non-conventional snake toxins which are of physiological, scientific and therapeutic importance.
Mapping drug or ligand binding sites within the nicotinic acetylcholine receptorIn the absence of atomic resolution structures of the nAChR, alone or in the presence of various ligands, alternate methods, including photoaffinity labelling and pharmacological and electrophysiological approaches, are needed to identify the complex anesthetic binding sites within their target receptors. By employing protein chemistry techniques such as photoaffinity labelling, gel electrophoresis, high performance liquid chromatography and protein sequencing, complemented by radio-isotope pharmacological binding assays, the sites of interactions between the nicotinic receptor and photo-activatable probes of the compound under study can be elaborately mapped out at the amino-acid level. Molecular models of the nicotinic acetylcholine receptor neurotransmitter-binding domain and the ion-channel pore region then enable remarkable three-dimensional visualization of these data. Two-electrode voltage clamp electrophysiology and basic molecular biology techniques are used to analyze the functional properties of wild-type and mutant or chemically modified nicotinic acetylcholine receptors in the presence and absence of the study compounds in order to validate the photo-labelling data. One major focus using the methodology described is the study of the molecular interaction of general anesthetic compounds (and their derivatives) with ligand-gated ion channels using the Torpedo electric organ nAChR as a convenient model. The broader objective underlying this work is to address the question of how general anesthetics exert their pharmacological actions to produce anesthesia as well as associated side effects. Other compounds similarly investigated include partial agonists and non-competitive antagonists of nAChRs.
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Amino acid residues in the ion channel of the nicotinic acetylcholine receptor photolabeled by azietomidate, a photoreactive analog of the general anesthetic drug, etomidate. Journal of Biological Chemistry (2004). |
Amino acid residues at the α/γ interface of the neurotransmitter-binding site of the nicotinic acetylcholine receptor photolabeled by a partial agonist benzolycholine derivative, Biochemistry (2005). |
RESEARCH TEAMTang Tzer Fong, BSc (Hon.)
Research Assistant.
COLLABORATIONS
- Prof. Jonathan B. Cohen
Department of Neurobiology, Harvard Medical School, Boston, MA., USA.
- Prof. Jan Tytgat
Laboratory for Toxicology, University of Leuven, Belgium.
- Prof. Daniel Bertrand
Department of Physiology, University of Geneve School of Medicine, Switzerland.
- Associate Prof. Peter Kuhn
Scripps Research Institute, La Jolla, CA., USA.
- Prof. Toshihiro Nohara / Associate Prof. Tsuyoshi Ikeda
Department of Pharmaceutical Sciences, University of Kumamoto, Japan.
- Prof. Manjunatha Kini
Department of Biological Sciences, National University of Singapore.
- Prof. P. Gopalakrishnakone
Department of Anatomy, School of Medicine, National University of Singapore.
- Assistant Prof. J. Sivaraman
Department of Biological Sciences, National University of Singapore.
SELECTED PUBLICATIONSSS Husain, S Nirthanan, D Ruesch, K Solt, Qi Cheng, GD Li, E Arevalo, RW Olsen, DE Raines, SA Forman, JB Cohen, KW Miller. Synthesis of trifluoromethylaryl diazirine and benzophenone derivatives of etomidate that are potent general anesthetics and effective photolabels for probing sites on ligand-gated ion channels. Journal of Medicinal Chemistry 49, 4818-4825 (2006).
I Andreeva, S Nirthanan, JB Cohen, SE Pedersen. Site-specificity of agonist-induced opening and desensitization of the Torpedo californica nicotinic acetylcholine receptor. Biochemistry 45, 195-204 (2006).
S Nirthanan, MR Ziebell, DC Chiara, FH Hong, JB Cohen. Photolabeling the Torpedo nicotinic acetylcholine receptor with 4-Azido-2,3,5,6-tetrafluoro-benzoylcholine, a partial agonist. Biochemistry 44, 13447-13456 (2005).
S Nirthanan, J Pil, Y Abdel-Mottaleb, Y Sugihara, JS Joseph, P Gopalakrishnakone, K Sato, J. Tytgat. Assignment of potassium channel blocking activity to κ-KTx1.3, a non-toxic homologue of κ-hefutoxin 1, from Heterometrus spinifer venom. Biochemical Pharmacology 69, 669-678 (2005).
MR Ziebell, S Nirthanan, SS Hussain, KW Miller, JB Cohen. Identification of binding sites in the nicotinic acetylcholine receptor of [3H]azietomidate, a photoactivable general anesthetic. Journal of Biological Chemistry 279, 17640-17649 (2004).
S Nirthanan, MCE Gwee. Three-finger neurotoxins and the nicotinic acetylcholine receptor, forty years on. Journal of Pharmacological Sciences 94, 1-17 (2004).
S Nirthanan, P Gopalakrishnakone, MCE Gwee, HE Khoo, E Charpantier, RM Kini, D Bertrand. Neuromuscular effects of candoxin, a novel toxin from the venom of the Malayan krait Bungarus candidus. British Journal of Pharmacology 139, 832-844 (2003).
S Nirthanan, E Charpantier, P Gopalakrishnakone, MCE Gwee, HE Khoo, LS Cheah, D Bertrand, RM Kini. Candoxin, a novel toxin from the venom of the Malayan krait (Bungarus candidus) is a reversible antagonist of muscle αβγδ and a poorly reversible antagonist of neuronal α7 nicotinic acetylcholine receptors. Journal of Biological Chemistry 277, 17811-17820 (2002).
S Nirthanan, JS Joseph, P Gopalakrishnakone, HE Khoo, LS Cheah, MCE Gwee. Biochemical and pharmacological characterization of the venom of the black scorpion (Heterometrus spinifer). Biochemical Pharmacology 63, 49-55 (2002). Featured in New Scientist 171 (v 2304), p18 (2001).
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