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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 associated with 8.B.28 family:

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. 15882064
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. 22229737
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. 18950653
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] 27916464
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. 21709136
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. 37689602
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] 33078946
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. 16325217
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. 19562324
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. 18798648
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. 23146020