Acetylcholine (ACh) is one of the most important neurotransmitters in the peripheral and central nervous systems. However, it is increasingly recognized that ACh is also a key molecule for signaling via nicotinic acetylcholine receptors (nAChRs) in non-neuronal cells. Mounting evidence indicates that subtypes of ?9-containing nAChRs are critical receptors of ACh in these non-neuronal cells. These receptors are implicated in a plethora of functions including immune function, cell migration and the stress response. Consequently, these nAChRs have been implicated in diseases ranging from chronic pain to cancer-cell proliferation. Unfortunately, study of these ?9-containing nAChRs is severely limited because of the lack of selective ligands. There are no ligands selective for human ?9-containing nAChRs. Furthermore, existing ligands are unable to discriminate among ?9-containing nAChR subtypes in any tested species. To address this problem, conotoxins that are antagonists of ?9-containing nAChRs will be exploited.
Aim 1 will develop selective antagonists for the human ?9 nAChR. This will be accomplished through iterative synthesis of analogs of ?-conotoxin RgIA and by development of newly discovered ?-conotoxins.
Aim 2 will characterize, for the first time, new families of conotoxins that target ?9-containing nAChRs. These will be developed to enable the selective block of subtypes of these nAChRs. A long-term goal is to use existing ligands, together with newly developed toxins to gain mechanistic insight into the hypothesized role of ?9-containing nAChRs in preventing chronic pain that ensues following nerve injury.
Aim 3 will use developed ligands to study the role of block of ?9-containing nAChRs in models of breast cancer.

Public Health Relevance

This proposal will develop novel molecules for the study of cell surface proteins known as alpha9 nicotinic receptors. These receptors regulate diverse functions including immune system function and cell growth. The ability to pharmacologically manipulate these receptors has the therapeutic potential to treat chronic pain and breast cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (40))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Salt Lake City
United States
Zip Code
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

Showing the most recent 10 out of 171 publications