17704452 (Howra Al-Badri), "Conotoxins"

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17704452 (Howra Al-Badri), "Conotoxins"

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  1. Advanced Physiology300851“Independent investigation topic”Ion channels “Conotoxins”Howra al-badri (17704452)

    Slide 1 - Advanced Physiology300851“Independent investigation topic”Ion channels “Conotoxins”Howra al-badri (17704452)

    • http://physrev.physiology.org/content/84/1/41
  2. Overview

    Slide 2 - Overview

    • What conotoxins are?
    • Types of conotoxins
    • What ion channels are involved?
    • How alpha-conotoxins work on ion channels
    • Classes of alpha-conotoxins “ImI”
    • The use of conotoxins
    • Summary
    • References
  3. Conotoxins?

    Slide 3 - Conotoxins?

    • What are they?
    • cone snail venom genus Conus
    • group of neurotoxic peptides
    • Contain 10 to 30 amino acid residues
    • One or more desulfide bonds
    • https://ferrebeekeeper.wordpress.com/tag/neurotoxin/
    • (Lebbe et al. 2014).
    • http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70183-8/fulltext?rss=yes
  4. types of conotoxins?

    Slide 4 - types of conotoxins?

    • Alpha-conotoxins
    • have 2 types of cysteine arrangements
    • Competitive nicotinic acetylcholine receptor antagonist
    • Delta-conotoxins
    • delays the inactivation of sodium channel
    • Kappa-conotoxins
    • potassium channel blocker
    • Omega-conotoxins
    • calcium channel blocker
    • Mu-conotoxins
    • Muscle-specific voltage-gated sodium channels
    • Useful for investigating voltage-dependent sodium channels of excitable tissues
    • (Gowd et al. 2008).
    • http://physrev.physiology.org/content/84/1/41
  5. Ion channel involved?

    Slide 5 - Ion channel involved?

    • Alpha-conotoxins act on different types of neuronal nicotinic acetylcholine receptors
    • the most diverse and largest group of conotoxins family
    • interact at the competitive site of the nicotinic acetylcholine receptors (nAChRs)
    • acetylcholine-binding protein (AChBP)
    • Polypeptides of a-conotoxins highly selective for blocking nAChRs and ligand-gated ion channels
    • A7 is a neuronal nicotinic acetylcholine receptor
    • has created much concern in medical field
    • distributed across cerebral cortex and hippocampus
    • (Luo et al. 2013), (Hopping et al. 2014).
    • Their binding sites at the interfaces among the α7 receptors in a homopentameric channel
    • http://www.nature.com/nrd/journal/v4/n8/fig_tab/nrd1797_F5.html
  6. Ion channel involved

    Slide 6 - Ion channel involved

    • Loops A, B and C areas of the primary sequence, contain the positive residues of the binding site of the α-face
    • In the acetylcholine-binding proteins, the stabilizations are established by the adjacent disulfide bonds in loop C
    • loop C a-conotoxins disulfide bonds interact with
    • (Lebbe et al, 2014)
    • (Luo et al. 2013).
  7. ImI conotoxin

    Slide 7 - ImI conotoxin

    • Class of apha-conotoxins
    • Has the greatest and complete structure-activity relationship concerning a7 nAChRs
    • It delineates a separate binding site above the loop C
    • Has an essential role for the contribution of:
    • Hydrophobic connections among several alpha conotoxins hydrophobic residues
    • Conserved proline
    • AChBPs’ residues in the aromatic cage
    • The amino acid residues needed for the interaction between ImI alpha conotoxins and nAChRs:
    • Aspartatic acid, tryptophan and arginine
    • (Lebbe et al, 2014)
    • (Yu, Craik and Kaas, 2011)
  8. The use of alpha Conotoxins

    Slide 8 - The use of alpha Conotoxins

    • Alpha-conotoxins used for therapeutic purpose & science investigations
    • Alpha-conotoxins used to design drugs to improve pain & cognition
    • Target many neurological disorders:
    • Parkinson’s disease
    • Alzheimer’s disease
    • attention deficit disorders
    • depression
    • Conotoxin drug Prialt®, treat intractable pain
    • Ziconitide Conus magus omega-conotoxins used for analgesia
    • Analogs of alpha-conotoxins MII nicotinic blocker conotoxin
    • effective in the treatment of Parkinson’s disease.
    • (Lebbe et al, 2014), (Fedosov et al. 2013), (Napier et al. 2012).
  9. The use of Conotoxins

    Slide 9 - The use of Conotoxins

    • Can be used for science investigation
    • Used as tools of research to determine how specific ion channels and receptors work
    • omega-conotoxins important in neuroscience studies
    • examine the sub-types of calcium channels
    • other conotoxins are used to study schizophrenia
    • (Livett, Gayler and Khalil, 2004), (Zaki et al. 2011).
    • http://www.fda.gov/ScienceResearch/AboutScienceResearchatFDA/
  10. Summary

    Slide 10 - Summary

    • What ion channel do alpha-conotoxins modulate?
    • Nicotinic acetylcholine receptors
    • How?
    • Interact at the competitive site of the nAChRs
    • Block ligand-gated ion channels and nAChRs
    • What are they used for?
    • Used to treat many neurological disorders
    • Used for science investigations
    • There different types of conotoxins each one of them:
    • Modulate different ion channels
    • Used for different purposes
    • http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(14)70183-8/fulltext?rss=yes
  11. References

    Slide 11 - References

    • Fedosov, A, Moshkovskiĭ, S, Kuznetsova, K, & Olivera, B 2013, '[Conotoxins: from the biodiversity of gastropods to new drugs]', Biomedit͡sinskai͡a Khimii͡a, 59, 3, pp. 267-294, MEDLINE, EBSCOhost, viewed 14 May 2015.
    • Gowd, KH, Dewan, KK, Iengar, P, Krishnan, KS, & Balaram, P 2008, 'Probing peptide libraries from Conus achatinus using mass spectrometry and cDNA sequencing: identification of delta and omega-conotoxins', Journal of Mass Spectrometry: JMS, vol. 43, no. 6, pp. 791-805, viewed 10 May 2015, DOI 10.1002/jms.1377
    • Hopping, G, Wang, CA, Hogg, RC, Nevin, ST, Lewis, RJ, Adams, DJ, & Alewood, PF 2014, 'Hydrophobic residues at position 10 of α-conotoxin PnIA influence subtype selectivity between α7 and α3β2 neuronal nicotinic acetylcholine receptors', Biochemical Pharmacology, vol. 91, no. 4, pp. 534-542, viewed 9 May 2015, DOI 10.1016/j.bcp.2014.07.025.
    • Lebbe, EM, Peigneur, S, Wijesekara, I, & Tytgat, J 2014, 'Conotoxins targeting nicotinic acetylcholine receptors: an overview', Marine Drugs, vol. 12, no. 5, pp. 2970-3004.
    • Livett, B, Gayler, K, & Khalil, Z 2004, 'Drugs from the sea: conopeptides as potential therapeutics', Current Medicinal Chemistry, 11, 13, pp. 1715-1723, viewed 14 May 2015, MEDLINE, EBSCOhost.
    • Luo, S, Zhangsun, D, Wu, Y, Zhu, X, Hu, Y, McIntyre, M, et al. 2013, 'Characterization of a novel α-conotoxin from conus textile that selectively targets α6/α3β2β3 nicotinic acetylcholine receptors', The Journal Of Biological Chemistry, vol. 288, no. 2, pp. 894-902, viewed 10 May 2015, MEDLINE, EBSCOhost, DOI 10.1074/jbc.M112.427898
  12. Reference

    Slide 12 - Reference

    • Napier, I, Klimis, H, Rycroft, B, Jin, A, Alewood, P, Motin, L, Adams, D, & Christie, M 2012, 'Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain', Neuropharmacology, 62, 7, pp. 2202-2207, viewed 13 May 2015, DOI 10.1016/j.neuropharm.2012.01.016
    • Yu, R, Craik, DJ, & Kaas, Q 2011, 'Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations', Plos Computational Biology, vol. 7, no. 3, p. e1002011. Available from: 10.1371/journal.pcbi.1002011.
    • Zaki, N, Wolfsheimer, S, Nuel, G, & Khuri, S 2011, 'Conotoxin protein classification using free scores of words and support vector machines', BMC Bioinformatics, 12, p. 217, viewed 14 May 2015, MEDLINE, EBSCOhost, DOI 10.1186/1471-2105-12-217