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). 

µ-Conotoxins are peptide toxins from the venoms of marine cone snails (genus Conus) that block NaV channels with nanomolar potency. Most species of the subgenera Textilia and Afonsoconus are difficult to acquire. McMahon et al. 2023 characterized new µ-conotoxins from species of the subgenera Textilia and Afonsoconus and investigated their selectivities for human NaV channels. Using RNA-seq of the venom gland of Conus (Textilia) bullatus, they identified 12 µ-conotoxin (or µ-conotoxin-like) sequences. Based on these sequences, primers were designed that were used to identify additional µ-conotoxin sequences from DNA extracted from historical specimens of species from Textilia and Afonsoconus. They synthesized six of these µ-conotoxins and tested their activity on human NaV1.1-NaV1.8. Five of the six synthetic peptides were potent blockers of human NaV channels. Of these, two peptides (BuIIIB and BuIIIE) were potent blockers of hNaV1.3. Three of the peptides (BuIIIB, BuIIIE and AdIIIA) had submicromolar activity on hNaV1.7 (McMahon et al. 2023).


This family belongs to the Conotoxin Superfamily.
 

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.
McMahon, K.L., H. O''Brien, C.I. Schroeder, J.R. Deuis, D. Venkatachalam, D. Huang, B.R. Green, P.K. Bandyopadhyay, Q. Li, M. Yandell, H. Safavi-Hemami, B.M. Olivera, I. Vetter, and S.D. Robinson. (2023). Identification of sodium channel toxins from marine cone snails of the subgenera Textilia and Afonsoconus. Cell Mol Life Sci 80: 287.
Peschel, A., F.C. Cardoso, A.A. Walker, T. Durek, M.R.L. Stone, N. Braga Emidio, P.E. Dawson, M. Muttenthaler, and G.F. King. (2020). Two for the Price of One: Heterobivalent Ligand Design Targeting Two Binding Sites on Voltage-Gated Sodium Channels Slows Ligand Dissociation and Enhances Potency. J Med Chem. [Epub: Ahead of Print]
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.
Wang, L., J. Liu, C. Pi, X. Zeng, M. Zhou, X. Jiang, S. Chen, Z. Ren, and A. Xu. (2009). Identification of a novel M-superfamily conotoxin with the ability to enhance tetrodotoxin sensitive sodium currents. Arch Toxicol 83: 925-932.
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). A heterobivalent ligand (mu-conotoxin KIIIA, which occludes the pore of the NaV channels, and an analogue of huwentoxin-IV, a spider-venom peptide that allosterically modulates channel gating (TC#8.B.3.1.3)) slows ligand dissociation and enhances potency (Peschel et al. 2020).

 

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)

 
8.B.28.1.8

Iota-conotoxin of 69 aas and 1 N-terminal TMS. Iota-conotoxins bind to voltage-gated sodium channels and act as agonists by shifting the voltage-dependence of activation to more hyperpolarized levels. This toxin enhances tetrodotoxin-sensitive sodium current in rat dorsal root ganglion neurons (Wang et al. 2009).

Iota-conotoxin of Conus litteratus (Lettered cone)

 
Examples:

TC#NameOrganismal TypeExample
8.B.28.2.1

Conotoxin of 80 aas

Conotoxin of Conus praecellens

 
8.B.28.2.2

Conotoxin precursor of 68 aas with one N-terminal TMS.

Conotoxin of Conus amadis