Presented to Dr. E. Toolson
& Biology 445
Stephen M. Sanchez
University of New Mexico
Spring 2009

www.portfolio.mvm.ed.ac.uk
Conus geographus using
Proboscis pub.pharm.kitasato-u.ac.jp:10080
Chemical structure of µ-conotoxin

 To discus background information including the source , chemical structure , and various classes of
Conotoxins .
 To offer ecological facts pertinent to evolutionary variation .
 A general introduction to the neuronal mechanisms of each
 A brief walkthrough ADAME
 To demonstrate therapeutic potential

 Marine cone snails - belonging to the genus Conus 4
 Predatory gastropod utilizing proboscis (venom-tongue)
-containing a class of conopeptides or conotoxins
 Over 500-1000 extant species

Range
 Tropical seas worldwide 4
-Also, have species in California and South Africa
Additional Information
 Only 100 of an estimated 50,000 toxins have been analyzed
 Single largest molluscan genus
 Have been collectibles for nearly 5000 years (Mesopotamia)
 Isolated in 1977 by J. Michael McIntosh at the age of 18
– Shores of Philippines

Conotoxin
 Concentrated into glands
 Paralytic neurotoxin
 Block specific ion channels at specific tissue types
 LD
50 approximately 25 µg/Kg 9

library.thinkquest.org:
Anatomical schematic of Conus geographus
• Highly developed toxin reservoir and duct
-Venom activated by enzymes in duct
• Siphon “smells” water
• Proboscis - harpoon containing venom

 Associated with shallow coral reef systems and mangrove swamps 10
 Dominant group
 Pisciverous diet establishes population density
 Threatened due to pharmacological needs and exploitive collecting 3

 Originally consumed worms only.
 Developed toxin to simply deter competition
-action at sodium or potassium gates, but not both.
 Toxin evolved
- resulted in a combination of sodium and K action
 Conus species capable of invoking incapacitation
-more adaptive than the competition.
 Selective pressure for novel toxin cocktails

 Cost of Venom
-results in high degree of specificity
 Possibly temperature controlled
 Peptides change day to day 8
 Potency and mixture determines whether cone feeds on worms, mollusk, or fish.
 Mixture delays the evolution of prey resistance

 Consists of small peptides
 Hydrophobic
 12-30 amino acid residues in length
 Multiple disulfide loops
 Single amino acid variations and highly conserved intercysteine “backbone”

www.mpg.de/bilderBerichteDokumente
 Alpha -competitive nicotinic acetylcholine receptor antagonists 8
 Developmental site nicotine and alcohol suppressant

 Delta
inhibits the inactivation of voltage-dependent Na channels.
-Hyperactivity, epilepsy
-keeping sodium channels open and interfering with action potential propagation

 Kappa
-inhibits K channels 14
-Preventing potassium efflux , disrupting resting potentials
Treatment of
Neurodegenerative disorders

www.mpg.de/bilderBerichteDokumente
 Mu
-inhibits voltagedependent Na channels in muscle.
-hyperactivity
 Treatments for epilepsy and cardiovascular disorders

 Omega
-inhibits N-type Ca channels on primary nociceptive nerves 6
-Hypertension
 Analgesic properties

 Conantonkins
-similar to alpha but in cases when glutamic acid is NT.
 Utilizes conkunitzins

A
 Naturally
 Intramuscularly through proboscis
 Aerosol
 Clinically
 intrathecally (1 st generation)
 Orally (2 nd generation)

D
 Cardiovascular circulation
 Supplemented by lymphatic system

A
Ligand-gated and voltage-gated
 Alpha: a9a10 nicotinic acetylcholine receptors at nerves and muscles
 Delta: sodium channels, site 6
 Kappa: Potassium channels

M
 Easily broken down by digestive processes
-peptides tend to dissociate easily in G.I.
-First pass.

E


Full recovery 7
Burning pain, local numbness, cardiac and respiratory distress, headache, nausea, stomach cramps
Fatalities
Conus geographus
Numbness without pain, stiffened lips, blurred vison, paralysis, coma.

www.nature.com/nature/journak

 Neuralgia 1
- associated with cancer, AIDS, injury, failed surgery & neuronal disorders.
 Epilepsy
 Mental illnesses 13
depression, Parkinson's and Alzheimer’s diseases schizophrenia
 Nicotine and alcohol addiction


- potency
- no addictive properties nor developed tolerance
- specificity: bind solely to neural, smooth muscle, and cardiac muscle.

• Important tool for defining ion channel function.
(neurobiologists)

• 1 Abbott, R. T., 'Mollusks and Medicine in World War II', in 1947 Ann. Rept.
Smithsonian Inst.
, 1948, pp. 325-38.
• 2 Cotton, B. C., Australian Recent and Tertiary Species of the Molluscan Family
Conidae , Adelaide, 1958, 4 pp.
• 3 Duda, T.F. Bingham, J.P. Livett, B.G. Kohn, A.T. et al. 13 Feb 2004. How much at risk are cone snails ? Science. Vol. 303 No. 5660:955-955.
 4 Imperial, J.S. Silverton, N. Olivera, B.M. et al. 2007. Using chemistry to reconstruct evolution: On the origins of fish-hunting in venomous cone snail s. Proceddings of the American Philosophical Society. Vol. 151 No. 2:185-200.
• 5 Jimenez, E.C., Olivera, B.M., Teichert R.W. 31 July 2007. alpha C-Conotoxin PrXA:
A new family of nicotinic acetylcholine receptor antagonists . Biochemistry.
Issue 30. Vol. 46:8717-8724.

• 6 Jones, R.M. Cartier, G.E. McIntosh, J.M. Bulaj, G. Farrar, V.E. Olivera, B.M. April
2001. Composition and therapeutic utility of conotoxins from genus Conus.
Patent status 1996-2000 . Expert Opinion on Therapeutic Patents. Issue 4 No.
11:603-623.
• 7 Kohn, A. J., 'Venomous Marine Snails of the Genus Conus ', in Hugh L. Keegan and
W. V. MacFarlane (eds), Venomous and Poisonous Animals and Noxious
Plants of the Pacific Region , Pergamon Press, Oxford, 1963, pp. 83-96.
• 8 Livett, B.J. Sandall, D.W. Keays, D. et al. 1 Dec 2006. Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor . Toxicon.
Vol.48 No. 7:810-829.
• 9 Santos, A.D. McIntosh, J.M. Hillard, D.R. Cruz, L.J. Olivera, B.M. A superfamily of conotoxins-Structural and functional divergence.
23 April 2004. Journal of
Biological Chemistry. Issue 17 Vol. 279:17596-17606.
• 10 Stackhouse, J., Australia's Venomous Wildlife , Paul Hamlyn, Sydney, 1970, 144 pp.

• 11 Teichert, R., Jacobsen, R., Terlau, H., Yoshikami, D., Olivera B.M. 1 Mar 2007.
Discovery and Characterization of the Short κA-Conotoxins
. Toxicon.
Issue 42. vol. 3:318-328.
• 12 Terlau H., Shon, K.J., Grilley, M., Stocker, M., Stuhmer, W., Oliveria, B.M. 9 May
1996. Strategy for rapid immobilization of prey by a fish-hunting marine snail .
Nature. Issue 6578. vol. 381:148-151.
 13 Twede, V.D. Miljanich, G. Olivera, B.M. et al. 2009. Neuroprotective and cardioprotective conopeptides: An emerging class of drug leads.
IDrugs.
Vol.12 No. 2:231-239.
• 14 Vabnick I., Trimmer, J.S., Schwarz T.L., Levinson, S.R. Risal, D., Shrager, P.
15 Jan 1999. Dynamic potassium channel distributions during axonal development prevent aberrant firing patterns . Journal of Neuroscience.
Issue. 2. Vol. 19:747-758.

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