Distinguished Professor of Biological Sciences
B.S. University of the Philippines
Ph.D. California Institute of Technology
Toto Olivera's Lab Page
Toto Olivera's PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Conotoxins, Molecular Neuroscience
Our major research interest is in molecular mechanisms that underlie nervous system function. Recent conceptual advances in defining key molecules important for signaling nervous systems makes it possible to address how multiple molecular components act sequentially or in concert to yield physiological function. To investigate this, we are developing a set of peptide ligands which target specific receptors and ion channel complexes of neurons; these peptides are found in the venoms of the predatory cone snails, Conus. The neurotoxins made by the venomous Conus (“conotoxins”) are small constrained peptides, each having high affinity for a particular receptor target. The major targets are ion channel families; thus, omega and mu conotoxins target Ca channel and Na receptor families, respectively.
The omega conotoxins have proven to be important research reagents for investigating molecular events that take place at synaptic junctions, since they block neurotransmitter release. Their voltage-gated Ca channel targets are the molecular components which transduce electrical signals of axons into the biochemical events at the presynaptic terminus. Different omega conotoxins are specific for different subtypes of voltage-gated Ca channels; one omega conotoxin originally discovered by our laboratory has been approved as a commercial drug for severe pain. Other families of Conus peptides affect the function of voltage-gated K+ channels.
Other classes of peptides from Conus venoms include the conantokins, the first peptide antagonists which target NMDA receptors, a major class of excitatory receptors in the vertebrate central nervous system, and the α-conotoxins, which target nicotinic acetylcholine receptors. Most Conus peptides are apparently specific for a particular subtype. The venom from a single Conus species contains more than 100 biologically active peptides; the ~700 species of Conus have >50,000 different peptides. The long-range goal is to use these toxins as an entrée for studying key molecules in the CNS. The fact that these toxins can be easily synthesized and labeled with reporter groups will permit a functional characterization of the key CNS targets of these peptides.
The precise mechanism that accounts for the biological activity of most biologically active peptides present in Conus venoms has not yet been determined. A major challenge in the next few years is to elucidate the molecular mechanisms through which the different peptides in Conus venom elicit their often striking behavioral effects.
- Teichert RW, Memon T, Aman JW, Olivera BM. (2014) Using Constellation Pharmacology to define comprehensively a somatosensory neuronal subclass. Proc. Natl. Acad. Sci. USA, 111(6): 2319-24.
- Aman JW, Imperial JS, Ueberheide B, Zhang MM, Aguilar M, Taylor D, Watkins M, Yoshikami D, Showers-Corneli P, Safavi-Hemami H, Biggs J, Teichert RW, Olivera BM. (2015) Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus. Proc. Natl. Acad. Sci. USA, 112(16): 5087-92.
- Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, Schlegel A, Imperial JS, Watkins M, Bandyopadhyay PK, Yandell M, Li Q, Purcell AW, Norton RS, Ellgaard L, Olivera BM. (2015) Specialized insulin is used for chemical warfare by fish-hunting cone snails. Proc. Natl. Acad. Sci. USA, 112(6): 1743-8.
- Teichert RW, Olivera BM, McIntosh JM, Bulaj G, Horvath MP. (2015) The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications In Venom to Drugs: Venom as a Source for the Development of Human Therapeutics. King, G. F., Ed. RSC Publishing: London, Vol. RSC Drug Discovery, pp 163-203.
- Bandyopadhyay PK, Stevenson BJ, Ownb JP, Cady MT, Watkins M, Olivera BM. (2008) The mitochondrial genome of Conus textile, coxI-coxII intergenic sequences and Conoidean evolution. Mol Phylogenet Evol, 46(1): 215-223.
- Olivera BM, Quik M, Vincler M, McIntosh JM. (2008) Subtype-selective conopeptides targeted to nicotinic receptors: Concerted discovery and biomedical applications. Channels (Austin) 2(2): 143-152.
- Olivera BM, Teichert RW. (2007) Diversity of the Neurotoxic Conus Peptides. Molecular Interventions, 7(5): 251-260.
- Buczek O, Yoshikami D, Bulaj G, Jimenez EC, Olivera BM. (2005) Posttranslational amino acid isomerization: a functionally important D-amino acid in an excitatory peptide. J. Biol. Chem, 280: 4247-53.
- Terlau H, Olivera BM. (2004) Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol. Rev, 84: 41-68.
- Bulaj G, Buczek O, Goodsell I, Jimenez EC, Jranski J, Garrett, JE, Olivera BM. (2003) Efficient oxidative folding of conotoxins and the radiation of venomous cone snails. Proc. Natl. Acad. Sci. USA, 100 (supp 2): 14562-69.
- Bandyopadhyay PK, Garrett JE, Shetty RP, Keate T, Walker CS, Olivera BM. (2002) g -Glutamyl carboxylation: an extracellular posttranslational modification that antedates the divergence of molluscs, arthropods and chordates. Proc. Natl. Acad. Sci. USA, 99: 1264-1269.
- Olivera BM. (2000) ω-Conotoxin MVIIA: from marine snail venom to analgesic drug. In Drugs from the Sea (Fusetani N, ed), Basel, Karger, 75-85.
- England LJ, Imperial J, Jacobsen R, Craig AG, Gulyas J, Akhtar M, Rivier J, Julius D, Olivera BM. (1998) Inactivation of a serotonin-gated ion channel by a polypeptide toxin from marine snails. Science, 281: 575-578.