Conus snails synthesize a bewildering variety of oligopeptides which target neuronal receptors and ion channels. The peptides contain an invariant framework of disulfides, while the remaining amino acid residues are relatively random and contain a gamut of post-translational modifications which are essential for their biological activity. Conus have evolved an efficient genetic means for encoding the variations. One of our goals is to understand how this diversity is generated. This will be achieved by determining the structure and sequence of the known conotoxin genes and their cDNAs. We will also attempt to characterize additional conotoxins by sequencing of selected cDNAs obtained from venom duct after elimination by subtractive hybridization of those that have been previously identified. We hope this knowledge will enable use to design efficient combinatorial methods for obtaining novel ligands of pharmacological import. A second goal of the project is to understand the mechanism of post- translational modification of the conotoxins, especially how gamma- carboxylation of glutamate is achieved. This modification is found in some conotoxins and in all conantokins, and is essential to their activity. Conus are the only non-mammalian species known to elaborate this modification. In mammals, gamma-carboxylated proteins are vital for the homeostasis of the blood coagulation cascade.
Our aim i s identify and characterize the enzymes necessary for gamma-carboxylation. This will be done by biochemical isolation of the enzyme and cloning of the gene. We hope the Conus gamma-carboxylation system is sufficiently similar to the mammalian system, and will also afford insight for the synthesis of active coagulation factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM048677-07
Application #
6107654
Study Section
Project Start
1999-01-01
Project End
1999-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Yan, Yijin; Peng, Can; Arvin, Matthew C et al. (2018) Nicotinic Cholinergic Receptors in VTA Glutamate Neurons Modulate Excitatory Transmission. Cell Rep 23:2236-2244
Hone, Arik J; McIntosh, J Michael (2018) Nicotinic acetylcholine receptors in neuropathic and inflammatory pain. FEBS Lett 592:1045-1062
Hone, Arik J; Talley, Todd T; Bobango, Janet et al. (2018) Molecular determinants of ?-conotoxin potency for inhibition of human and rat ?6?4 nicotinic acetylcholine receptors. J Biol Chem 293:17838-17852
Banala, Sambashiva; Arvin, Matthew C; Bannon, Nicholas M et al. (2018) Photoactivatable drugs for nicotinic optopharmacology. Nat Methods 15:347-350
Hone, Arik J; Servent, Denis; McIntosh, J Michael (2018) ?9-containing nicotinic acetylcholine receptors and the modulation of pain. Br J Pharmacol 175:1915-1927
Espino, Samuel S; Robinson, Samuel D; Safavi-Hemami, Helena et al. (2018) Conopeptides promote itch through human itch receptor hMgprX1. Toxicon 154:28-34
Richter, Katrin; Sagawe, Sabrina; Hecker, Andreas et al. (2018) C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation. Front Immunol 9:1604
Hiller, Sebastian Daniel; Heldmann, Sarah; Richter, Katrin et al. (2018) ?-Nicotinamide Adenine Dinucleotide (?-NAD) Inhibits ATP-Dependent IL-1? Release from Human Monocytic Cells. Int J Mol Sci 19:
Peng, Can; Yan, Yijin; Kim, Veronica J et al. (2018) Gene editing vectors for studying nicotinic acetylcholine receptors in cholinergic transmission. Eur J Neurosci :
Chen, De-Jie; Gao, Fen-Fei; Ma, Xiao-Kuang et al. (2018) Pharmacological and functional comparisons of ?6/?3?2?3-nAChRs and ?4?2-nAChRs heterologously expressed in the human epithelial SH-EP1 cell line. Acta Pharmacol Sin 39:1571-1581

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