Frontiers in Pharmacology (Jan 2019)
Conopeptides [V11L;V16D]ArIB and RgIA4: Powerful Tools for the Identification of Novel Nicotinic Acetylcholine Receptors in Monocytes
Abstract
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 α-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 α7∗ and α9∗ 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 α7∗ and α9∗ nAChRs, respectively, function as ligand-gated ion channels, in immune cells ligand-evoked ion currents have not been demonstrated. Instead, different metabotropic functions of α7∗ and α9∗ nAChRs have been described in monocytic cells including the inhibition of ATP-induced ion currents, inflammasome activation, and interleukin-1β (IL-1β) release. In addition to conventional nAChR agonists, diverse compounds containing a phosphocholine group inhibit monocytic IL-1β 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 α9, α7, and/or α10 subunits inhibits ATP-induced IL-1β release. These results have been corroborated utilizing gene-deficient mice and small interfering RNA. Targeted re-engineering of native α-conotoxins has resulted in excellent tools for nAChR research as well as potential therapeutics. ∗indicates possible presence of additional subunits.
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