Journal
FRONTIERS IN PHARMACOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2018.01499
Keywords
alpha-conotoxin; CHRNA7; CHRNA9; CHRNA10; immunomodulation; interleukin-1 beta; P2X7 receptor
Categories
Funding
- German Research Foundation [GR 1094/7-1]
- German Center for Lung Research (DZL)
- Fritz-Thyssen-Stiftung, Germany [50.18.0.004MN]
- National Institutes of Health [GM48677, GM103801]
- Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-17-1-0413]
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Venomous marine snails of the genus Conus employ small peptides to capture prey, mainly osteichthyes, mollusks, and worms. A subset of these peptides known as a -conotoxins, are antagonists of nicotinic acetylcholine receptors (nAChRs). These disulfide-rich peptides provide a large number of evolutionarily refined templates that can be used to develop conopeptides that are highly selective for the various nAChR subtypes. Two such conopeptides, namely [V11L;V16D] ArIB and RgIA4, have been engineered to selectively target mammalian alpha 7* and alpha 9* nAChRs, respectively, and have been used to study the functional roles of these subtypes in immune cells. Unlike in neurons and cochlear hair cells, where alpha 7* and alpha 9* nAChRs, respectively, function as ligand-gated ion channels, in immune cells ligand-evoked ion currents have not been demonstrated. Instead, different metabotropic functions of alpha 7* and alpha 9* nAChRs have been described in monocytic cells including the inhibition of ATP-induced ion currents, inflammasome activation, and interleukin-1 beta (IL-beta) release. In addition to conventional nAChR agonists, diverse compounds containing a phosphocholine group inhibit monocytic IL-beta release and include dipalmitoyl phosphatidylcholine, palmitoyl lysophosphatidylcholine, glycerophosphocholine, phosphocholine, phosphocholine-decorated lipooligosaccharides from Haemophilus influenzae, synthetic phosphocholine-modified bovine serum albumin, and the phosphocholine-binding C-reactive protein. In monocytic cells, the effects of [V11L; V16D] ArIB and RgIA4 suggested that activation of nAChRs containing alpha 9, alpha 7, and/or alpha 10 subunits inhibits ATP-induced IL-1 beta release. These results have been corroborated utilizing gene-deficient mice and small interfering RNA. Targeted re-engineering of native alpha-conotoxins has resulted in excellent tools for nAChR research as well as potential therapeutics. *indicates possible presence of additional subunits.
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