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RESEARCH INTERESTS
Biochemistry; Neurobiology
Conopeptides
Key signaling molecules in the central nervous system
Ion channels and receptors
PUBLICATIONS
Poster
Role of Propeptide & Protein Disulfide Isomerase/Oxidative Folding of Conotoxins
Our major interest is in molecular mechanisms underlying nervous system function. Recent conceptual and technical advances have greatly accelerated progress in defining key molecules important for signaling in the mammalian central nervous system, making it possible to address how molecular components can be combined 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 are found in the venoms of the predatory cone snails, Conus. The neurotoxins made by the venomous Conus are small constrained peptides, each having high affinity for a particular receptor target. One group of targets are the ion channel families found in neurons. Correspondingly, Conus peptide families characterized by our laboratories target these ion channel families: for example, w- and m-conotoxins and conantokins for Ca channel, Na channel and glutamate receptor families, respectively.
The w-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. Because different w-conotoxins are specific for different subtypes of voltage-gated Ca channels, these peptides can be used to investigate which voltage-gated Ca channels control neurotransmitter release in a given synapse. One w-conotoxin originally discovered by our laboratory may be approved as a commercial drug for pain in the near future.
Another class of peptides from Conus venoms are the conantokins, the first peptide antagonists which target to the major excitatory receptors in the vertebrate central nervous system, glutamate receptors. The conantokins selectively inhibit a subtype of glutamate receptor, the NMDA (N-methyl-D-aspartate) receptor, which are ligand-gated Ca channels. Conantokins cause rather striking biological effects: in young mice, they induce sleep, but in adult mice, these peptides induce a very characteristic hyperactivity when introduced into the central nervous system. The strikingly different behavioral effects of conantokins suggest either that different subtypes of NMDA receptors are present in young animals vs. adults, or that there is a drastic change in the circuitry involving NMDA receptors between 2-3 weeks of age. One conantokin is in early clinical trials as a potential drug for intractable epilepsy.
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.
Selected Publications
Olivera, B.M., W.R. Gray, R. Zeikus, J.M. McIntosh, J. Varga, J. Rivier, V. de Santos and L.J. Cruz (1985) Peptide neurotoxins from fish-hunting cone snails. Science 230:1338-43.
Olivera, B.M., J. Rivier, C. Clark, C.A. Ramilo, G.P. Corpuz, F.C.
Abogadie, E.E. Mena, S.R. Woodward, D.R. Hillyard and L.J. Cruz (1990)
Diversity of Conus neuropeptides. Science 249:257-63.
Olivera, B.M., G. Miljanich, J. Ramachandran and M.E. Adams (1994) Calcium channel diversity and neurotransmitter release: The w-conotoxins and w-agatoxins. Ann. Rev. Biochem. 63:823-67.
Terlau, H., K. Shon, M. Grilley, M. Stocker, W. Stühmer and B.M. Olivera
(1996) Strategy for rapid immobilization of prey by a fish-hunting cone
snail. Nature 381:148-51.
Olivera, B.M. (1997) E.E. Just Lecture - Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of
neuropharmacology. Mol. Biol. Cell 8:2101-09.
McIntosh, J.M., A.D. Santos and B.M. Olivera (1999) Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes. Annu. Rev. Biochem. 68:59-88.
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