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)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koduri, Sailaja
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
Zip Code
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
Siebers, Kathrin; Fink, Bijan; Zakrzewicz, Anna et al. (2018) Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1? via CD36 and Nicotinic Acetylcholine Receptors. Front Immunol 9:877
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:

Showing the most recent 10 out of 277 publications