8.B.28 The Mu-Conotoxin (Mu-Conotoxin) Family 

The neurotoxic cone snail peptide mu-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4; TC# 1.A.1.10.4) channels. The related conopeptides mu-PIIIA and mu-SIIIA, however, exhibit a wider activity spectrum by also inhibiting the neuronal NaV channels NaV1.2 and NaV1.7. Leipold et al. 2016 demonstrated that those mu-conopeptides with a broader target range also antagonize select subtypes of voltage-gated potassium channels of the KV1 family: mu-PIIIA and mu-SIIIA inhibited KV1.1 and KV1.6 channels in the nanomolar range, while being inactive on subtypes KV1.2-1.5 and KV2.1. Construction and electrophysiological evaluation of chimeras between KV1.5 and KV1.6 revealed that these toxins block KV channels involving their pore regions; the subtype specificity is determined in part by the sequence close to the selectivity filter but predominantly by the so-called turret domain, i.e. the extracellular loop connecting the pore with transmembrane segment S5. Conopeptides mu-SIIIA and mu- PIIIA, thus, are not specific for NaV channels (Leipold et al. 2016).



This family belongs to the .

 

References:

Bulaj, G., P.J. West, J.E. Garrett, M. Watkins, M. Marsh, M.M. Zhang, R.S. Norton, B.J. Smith, D. Yoshikami, and B.M. Olivera. (2005). Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels. Biochemistry 44: 7259-7265.

Favreau, P., E. Benoit, H.G. Hocking, L. Carlier, D. D'' hoedt, E. Leipold, R. Markgraf, S. Schlumberger, M.A. Córdova, H. Gaertner, M. Paolini-Bertrand, O. Hartley, J. Tytgat, S.H. Heinemann, D. Bertrand, R. Boelens, R. Stöcklin, and J. Molgó. (2012). A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors. Br J Pharmacol 166: 1654-1668.

Holford, M., M.M. Zhang, K.H. Gowd, L. Azam, B.R. Green, M. Watkins, J.P. Ownby, D. Yoshikami, G. Bulaj, and B.M. Olivera. (2009). Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus. Toxicon 53: 90-98.

Leipold, E., F. Ullrich, M. Thiele, A.A. Tietze, H. Terlau, D. Imhof, and S.H. Heinemann. (2016). Subtype-specific block of voltage-gated K+ channels by μ-conopeptides. Biochem. Biophys. Res. Commun. [Epub: Ahead of Print]

McArthur, J.R., G. Singh, D. McMaster, R. Winkfein, D.P. Tieleman, and R.J. French. (2011). Interactions of key charged residues contributing to selective block of neuronal sodium channels by μ-conotoxin KIIIA. Mol Pharmacol 80: 573-584.

Wang, C.Z., H. Zhang, H. Jiang, W. Lu, Z.Q. Zhao, and C.W. Chi. (2006). A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat tetrodotoxin-resistant sodium channels. Toxicon 47: 122-132.

Yao, S., M.M. Zhang, D. Yoshikami, L. Azam, B.M. Olivera, G. Bulaj, and R.S. Norton. (2008). Structure, dynamics, and selectivity of the sodium channel blocker mu-conotoxin SIIIA. Biochemistry 47: 10940-10949.

Zhang, M.M., M.J. Wilson, L. Azam, J. Gajewiak, J.E. Rivier, G. Bulaj, B.M. Olivera, and D. Yoshikami. (2013). Co-expression of Na(V)β subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins. Br J Pharmacol 168: 1597-1610.

Examples:

TC#NameOrganismal TypeExample
8.B.28.1.1

Mu-conotoxin (Mu-conopeptide) SIIIA of 73 aas.  Inhibits both Na+ and K+ channels specifically; thus Kv1.1 and Kv1.6 are inhibited, but other K+ channels tested were not (Leipold et al. 2016).  Of Na+ channels, this toxin moderately blocks rNav1.1/SCN1A, rNav1.2/SCN2A, rNav1.3/SCN3A, rNav1.4/SCN4A, and mNav1.6/SCN8A (Wang et al. 2006; Yao et al. 2008; Bulaj et al. 2005).

Conotoxin SIIIA of Conus striatus (Striated cone)

 
8.B.28.1.2

Conotoxin (conopeptide) PIIIA of 73 aas. Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently but reversibly blocks rNav1.4/SCN4A and moderately blocks rNav1.1/SCN1A, rNav1.2/SCN2A, rNav1.3/SCN3A, mNav1.6/SCN8A, and h/rNav1.7/SCN9A. The block of SCN1A, SCN2A, and SCN8A is modified when beta-subunits are coexpressed with alpha subunits. 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 are less potent (also compared to channels without beta subunits). This peptide causes flaccid paralysis in both mice and fish (Holford et al. 2009; Favreau et al. 2012; Zhang et al. 2013; Leipold et al. 2016).

Conotoxin PIIIA of Conus purpurascens (Purple cone)

 
8.B.28.1.3

Conotoxin (conopeptide) Mu-GIIIA of 74 aas. Specifically blocks skeletal muscle voltage-gated sodium (NaV1.4) channels (Leipold et al. 2016).

Conotoxin Mu-GIIIA of Conus geographus (Geography cone) (Nubecula geographus)

 
8.B.28.1.4

Mu-conotoxin KIIIA of 18 aas. This toxin potently blocks rNav1.2/SCN2A and rNav1.4/SCN4A but also moderately blocks rNav1.1/SCN1A, rNav1.3/SCN3A, rNav1.5/SCN5A, mNav1.6/SCN8A, and rNav1.7/SCN9A. On rNav1.2/SCN2A, it produces a block that is only partially reversible. The block of SCN9A is modified when beta-subunits are coexpressed with the alpha subunit (McArthur et al. 2011; Zhang et al. 2013).

Mu-conotoxin KIIIA of Conus kinoshitai (Kinoshita's cone)

 
8.B.28.1.5

M superfamily MLKM group conopeptide Vx3-A01 of 70 aas and 1 N-terminal TMS

M superfamily MLKM group conopeptide Vx3-A01 of Conus vexillum (Flag cone)

 
8.B.28.1.6

M-superfamily conotoxin of 71 aas and 1 TMS.

M-superfamily conotoxin of Conus ebraeus (Hebrew cone)

 
8.B.28.1.7

Conotoxin Vn.MLKM-04 of 69 aas and 1 TMS.

Cnotoxin VNMLKM-04 of Conus ventricosus (Mediterranean cone)