This program uses biodiversity for basic biomedical research, with direct therapeutic and diagnostic applications. The program focuses on the discovery, characterization and development of powerful pharmacological agents targeted to signaling molecules (e.g., receptors and ion channels). The source of these are >10,000 species of venomous marine snails (particularly the cone snails, Conus). The venoms of these snail are complex, containing ca. 100 different peptides ("conopeptides, conotoxins"), each highly selective for a particular receptor or ion channel. Because of the molecular complexity of their targets, conopeptides have been particularly useful for understanding the function of molecular isoforms of these signaling molecules. Increasingly, they have become standard reagents in neuropharmacology, and serve as an essential complement to molecular genetics for understanding neuronal function and the circuitry of the nervous system. The basis of physiological circuits is chemical and electrical communication between cells, which is mediated by a vast diversity of different signaling molecules. A barrier to investigating physiological circuits is the intrinsic molecular complexity of receptors and ion channels;protein subunits encoded by gene families form multimeric complexes (most commonly tetramers or pentamers). Because of the intrinsic combinatorial nature of functional multimeric ion channel complexes, a large complement of different receptors and ion channels can be generated from a few genes. For understanding receptor and ion channel function, it is optimal to use highly selective ligands that distinguish between closely-related receptor and ion channel isoforms. Our program uses the peptides that have been evolved by venomous marine snails to interact with their prey, predators and competitors as a prime source of such highly selective ligands. It is estimated that there are over 2 million biologically active peptides in marine snail venoms, which are the basis for developing the pharmacological tools to investigate the molecular complexity of receptors and ion channels, and to define the functional roles of the vast array of receptor/ion channel isoforms. A sufficiently large number of diversely targeted conopeptides have been developed by this program to allow these to be used in combination. The primary goal is to use these conopeptide combinations to investigate the distinct complement of receptor/ion channel isoforms present in each neuronal subclass. This leads to a new paradigm for using pharmacologically active compounds, which we refer to as "Constellation Pharmacology".

Public Health Relevance

This research program focuses on using marine biodiversity (i.e., 13,000 species of venomous marine snails) for biomedical applications. Compounds discovered in our research have promise for understanding and treating pain. In the long term, our goal is to enable following the progression of diseases of the nervous system, and ultimately, to learn to halt the disease progression. OVERALL PROGRAM:

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-MDCN-G (40))
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Dunsmore, Sarah
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University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
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Engle, Staci E; McIntosh, J Michael; Drenan, Ryan M (2015) Nicotine and ethanol cooperate to enhance ventral tegmental area AMPA receptor function via ?6-containing nicotinic receptors. Neuropharmacology 91:13-22
Olivera, Baldomero M; Showers Corneli, Patrice; Watkins, Maren et al. (2014) Biodiversity of cone snails and other venomous marine gastropods: evolutionary success through neuropharmacology. Annu Rev Anim Biosci 2:487-513
Marks, Michael J; Grady, Sharon R; Salminen, Outi et al. (2014) ?6?2*-subtype nicotinic acetylcholine receptors are more sensitive than ?4?2*-subtype receptors to regulation by chronic nicotine administration. J Neurochem 130:185-98
Di Cesare Mannelli, Lorenzo; Cinci, Lorenzo; Micheli, Laura et al. (2014) ?-conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement. Pain 155:1986-95
Teichert, Russell W; Memon, Tosifa; Aman, Joseph W et al. (2014) Using constellation pharmacology to define comprehensively a somatosensory neuronal subclass. Proc Natl Acad Sci U S A 111:2319-24
Imperial, Julita S; Cabang, April B; Song, Jie et al. (2014) A family of excitatory peptide toxins from venomous crassispirine snails: using Constellation Pharmacology to assess bioactivity. Toxicon 89:45-54
Muldoon, P P; Jackson, K J; Perez, E et al. (2014) The ?3?4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies. Br J Pharmacol 171:3845-57
Chang, Yi-Pin; Banerjee, Jayati; Dowell, Cheryl et al. (2014) Discovery of a potent and selective ?3?4 nicotinic acetylcholine receptor antagonist from an ?-conotoxin synthetic combinatorial library. J Med Chem 57:3511-21
Luo, Sulan; Zhangsun, Dongting; Schroeder, Christina I et al. (2014) A novel ?4/7-conotoxin LvIA from Conus lividus that selectively blocks ?3?2 vs. ?6/?3?2?3 nicotinic acetylcholine receptors. FASEB J 28:1842-53
Hernández-Vivanco, Alicia; Hone, Arik J; Scadden, Mick L et al. (2014) Monkey adrenal chromaffin cells express ?6?4* nicotinic acetylcholine receptors. PLoS One 9:e94142

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