Science and Research

Conopeptides [V11L;V16D]ArIB and RgIA4: Powerful Tools for the Identification of Novel Nicotinic Acetylcholine Receptors in Monocytes

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 alpha-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 alpha7( *) and alpha9( *) 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 alpha7( *) and alpha9( *) nAChRs, respectively, function as ligand-gated ion channels, in immune cells ligand-evoked ion currents have not been demonstrated. Instead, different metabotropic functions of alpha7( *) and alpha9( *) nAChRs have been described in monocytic cells including the inhibition of ATP-induced ion currents, inflammasome activation, and interleukin-1beta (IL-1beta) release. In addition to conventional nAChR agonists, diverse compounds containing a phosphocholine group inhibit monocytic IL-1beta 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 alpha9, alpha7, and/or alpha10 subunits inhibits ATP-induced IL-1beta 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.

  • Grau, V.
  • Richter, K.
  • Hone, A. J.
  • McIntosh, J. M.

Keywords

  • Chrna10
  • Chrna7
  • Chrna9
  • P2X7 receptor
  • immunomodulation
  • interleukin-1beta
  • alpha-conotoxin
Publication details
DOI: 10.3389/fphar.2018.01499
Journal: Front Pharmacol
Pages: 1499 
Work Type: Original
Location: UGMLC
Disease Area: ROR
Partner / Member: JLU
Access-Number: 30687084
See publication on PubMed

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