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).
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)
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)
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)
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)
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)
M-superfamily conotoxin of 71 aas and 1 TMS.
M-superfamily conotoxin of Conus ebraeus (Hebrew cone)
Conotoxin Vn.MLKM-04 of 69 aas and 1 TMS.
Cnotoxin VNMLKM-04 of Conus ventricosus (Mediterranean cone)
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)