| Specific Function
| Mu-conotoxin KIIIA-P1: mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks Nav1.2/SCN2A (IC(50)~5 nM) and Nav1.4/SCN4A (IC(50)=20-90 nM) (PubMed:17724025, PubMed:19221510, PubMed:21781281, PubMed:21709136, PubMed:25658507). It moderately blocks Nav1.1/SCN1A, mNav1.6/SCN8A, and Nav1.7/SCN9A (PubMed:17724025, PubMed:21781281, PubMed:21709136, PubMed:21652775, PubMed:23146020, PubMed:25658507). It also shows a very low activity on Nav1.3/SCN3A (PubMed:17724025, PubMed:21781281). This toxin binds a microsite within the pore different from the tetrodotoxin binding site 1 (tested on Nav1.2) (PubMed:19221510). The block is partial, with a residual current that can be completely blocked by TTX (PubMed:19221510). The toxin probably docks at a more superficial site in the outer vestibule of the channel than does TTX (PubMed:19221510). On rNav1.2/SCN2A, it produces a block that is only partially reversible. The block of Nav1.7 is modified when beta-subunits are coexpressed with the alpha subunit (PubMed:23146020). Hence, blocks of channels containing beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing beta-2 and beta-4 subunits are less potent (compared to channels without beta subunits) (PubMed:23146020).Mu-conotoxin KIIIA-P2: This toxin potently blocks Nav1.2/SCN2A (Kd=230 nM) and Nav1.4/SCN4A (Kd=830 nM). It also moderately blocks Nav1.7/SCN9A (Kd=1.57 uM). In addition, this toxin may also inhibit other sodium channels, as does Mu-conotoxin KIIIA-P1.Mu-conotoxin KIIIB-P1: This toxin potently blocks Nav1.2/SCN2A (Kd=470 nM). In addition, this toxin may also inhibit other sodium channels, as does Mu-conotoxin KIIIA-P1.Mu-conotoxin KIIIB-P2: This toxin potently blocks Nav1.2/SCN2A (Kd=26 nM). In addition, this toxin may also inhibit other sodium channels, as does Mu-conotoxin KIIIA-P1. |
| General References
| - Bulaj G, West PJ, Garrett JE, Watkins M, Zhang MM, Norton RS, Smith BJ, Yoshikami D, Olivera BM: Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels. Biochemistry. 2005 May 17;44(19):7259-65. doi: 10.1021/bi0473408. [PubMed:15882064 ]
- Zhang MM, Green BR, Catlin P, Fiedler B, Azam L, Chadwick A, Terlau H, McArthur JR, French RJ, Gulyas J, Rivier JE, Smith BJ, Norton RS, Olivera BM, Yoshikami D, Bulaj G: Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels. J Biol Chem. 2007 Oct 19;282(42):30699-706. doi: 10.1074/jbc.M704616200. Epub 2007 Aug 27. [PubMed:17724025 ]
- Holford M, Zhang MM, Gowd KH, Azam L, Green BR, Watkins M, Ownby JP, Yoshikami D, Bulaj G, Olivera BM: Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus. Toxicon. 2009 Jan;53(1):90-8. doi: 10.1016/j.toxicon.2008.10.017. Epub 2008 Nov 20. [PubMed:18950653 ]
- Van Der Haegen A, Peigneur S, Tytgat J: Importance of position 8 in mu-conotoxin KIIIA for voltage-gated sodium channel selectivity. FEBS J. 2011 Sep;278(18):3408-18. doi: 10.1111/j.1742-4658.2011.08264.x. Epub 2011 Aug 24. [PubMed:21781281 ]
- McArthur JR, Singh G, McMaster D, Winkfein R, Tieleman DP, French RJ: Interactions of key charged residues contributing to selective block of neuronal sodium channels by mu-conotoxin KIIIA. Mol Pharmacol. 2011 Oct;80(4):573-84. doi: 10.1124/mol.111.073460. Epub 2011 Jun 27. [PubMed:21709136 ]
- Wilson MJ, Yoshikami D, Azam L, Gajewiak J, Olivera BM, Bulaj G, Zhang MM: mu-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10302-7. doi: 10.1073/pnas.1107027108. Epub 2011 Jun 7. [PubMed:21652775 ]
- Zhang MM, Wilson MJ, Azam L, Gajewiak J, Rivier JE, Bulaj G, Olivera BM, Yoshikami D: Co-expression of Na(V)beta subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking mu-conotoxins. Br J Pharmacol. 2013 Apr;168(7):1597-610. doi: 10.1111/bph.12051. [PubMed:23146020 ]
- Murray JK, Ligutti J, Liu D, Zou A, Poppe L, Li H, Andrews KL, Moyer BD, McDonough SI, Favreau P, Stocklin R, Miranda LP: Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel. J Med Chem. 2015 Mar 12;58(5):2299-314. doi: 10.1021/jm501765v. Epub 2015 Feb 19. [PubMed:25658507 ]
- Khoo KK, Gupta K, Green BR, Zhang MM, Watkins M, Olivera BM, Balaram P, Yoshikami D, Bulaj G, Norton RS: Distinct disulfide isomers of mu-conotoxins KIIIA and KIIIB block voltage-gated sodium channels. Biochemistry. 2012 Dec 11;51(49):9826-35. doi: 10.1021/bi301256s. Epub 2012 Nov 28. [PubMed:23167564 ]
- Pan X, Li Z, Huang X, Huang G, Gao S, Shen H, Liu L, Lei J, Yan N: Molecular basis for pore blockade of human Na(+) channel Nav1.2 by the mu-conotoxin KIIIA. Science. 2019 Mar 22;363(6433):1309-1313. doi: 10.1126/science.aaw2999. Epub 2019 Feb 14. [PubMed:30765605 ]
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