8.B.32.  The Nicotinic Acetylcholine Receptor-targeting Alpha-Conotoxin (A-Conotoxin) Family

α-Conotoxins bind to neuronal and muscular nicotinic acetylcholine receptors (nAChR) and inhibit them. These toxins block neuronal mammalian nAChRs (alpha-6/alpha-3-beta-2-beta-3 (0.39 nM) > alpha-3-beta-2 > alpha-3-beta-4 = alpha-4-beta-2) (Cartier et al. 1996; Kuryatov et al. 2000;  McIntosh et al. 2004; Shiembob et al. 2006). In addition, specific members of the family bind to and influence the activities of GABAB GPCRs, K+ channels, and neuronal VGSCs (Robinson and Norton 2014).

 

 


This family belongs to the Conotoxin Superfamily.
 

References:

Alonso, D., Z. Khalil, N. Satkunanthan, and B.G. Livett. (2003). Drugs from the sea: conotoxins as drug leads for neuropathic pain and other neurological conditions. Mini Rev Med Chem 3: 785-787.
Cartier, G.E., D. Yoshikami, W.R. Gray, S. Luo, B.M. Olivera, and J.M. McIntosh. (1996). A new α-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J. Biol. Chem. 271: 7522-7528.
Guo, M., J. Yu, X. Zhu, D. Zhangsun, and S. Luo. (2021). Characterization of an α 4/7-Conotoxin LvIF from That Selectively Blocks α3β2 Nicotinic Acetylcholine Receptor. Mar Drugs 19:.
Kuryatov, A., F. Olale, J. Cooper, C. Choi, and J. Lindstrom. (2000). Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology 39: 2570-2590.
Liu, Z., H. Li, N. Liu, C. Wu, J. Jiang, J. Yue, Y. Jing, and Q. Dai. (2012). Diversity and evolution of conotoxins in Conus virgo, Conus eburneus, Conus imperialis and Conus marmoreus from the South China Sea. Toxicon 60: 982-989.
Luo, S., D. Zhangsun, C.I. Schroeder, X. Zhu, Y. Hu, Y. Wu, M.M. Weltzin, S. Eberhard, Q. Kaas, D.J. Craik, J.M. McIntosh, and P. Whiteaker. (2014). A novel α4/7-conotoxin LvIA from Conus lividus that selectively blocks α3β2 vs. α6/α3β2β3 nicotinic acetylcholine receptors. FASEB J. 28: 1842-1853.
McIntosh, J.M., C. Dowell, M. Watkins, J.E. Garrett, D. Yoshikami, and B.M. Olivera. (2002). Alpha-conotoxin GIC from Conus geographus, a novel peptide antagonist of nicotinic acetylcholine receptors. J. Biol. Chem. 277: 33610-33615.
McIntosh, J.M., L. Azam, S. Staheli, C. Dowell, J.M. Lindstrom, A. Kuryatov, J.E. Garrett, M.J. Marks, and P. Whiteaker. (2004). Analogs of α-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol Pharmacol 65: 944-952.
Peng, C., S. Tang, C. Pi, J. Liu, F. Wang, L. Wang, W. Zhou, and A. Xu. (2006). Discovery of a novel class of conotoxin from Conus litteratus, lt14a, with a unique cysteine pattern. Peptides 27: 2174-2181.
Rashid, M.H., S. Mahdavi, and S. Kuyucak. (2013). Computational studies of marine toxins targeting ion channels. Mar Drugs 11: 848-869.
Robinson, S.D. and R.S. Norton. (2014). Conotoxin gene superfamilies. Mar Drugs 12: 6058-6101.
Shiembob, D.L., R.L. Roberts, C.W. Luetje, and J.M. McIntosh. (2006). Determinants of α-conotoxin BuIA selectivity on the nicotinic acetylcholine receptor beta subunit. Biochemistry 45: 11200-11207.
Teichert, R.W., E. López-Vera, J. Gulyas, M. Watkins, J. Rivier, and B.M. Olivera. (2006). Definition and characterization of the short alphaA-conotoxins: a single residue determines dissociation kinetics from the fetal muscle nicotinic acetylcholine receptor. Biochemistry 45: 1304-1312.
Teichert, R.W., R. Jacobsen, H. Terlau, D. Yoshikami, and B.M. Olivera. (2007). Discovery and characterization of the short kappaA-conotoxins: a novel subfamily of excitatory conotoxins. Toxicon 49: 318-328.
Turner, M., S. Eidemiller, B. Martin, A. Narver, J. Marshall, L. Zemp, K.A. Cornell, J.M. McIntosh, and O.M. McDougal. (2009). Structural basis for α-conotoxin potency and selectivity. Bioorg Med Chem 17: 5894-5899.
Xu, W., M. Wang, X. Li, R. He, R.B. Ding, J. Bao, D. Zhangsun, and S. Luo. (2025). α-Conotoxin TxIB Reversed Nicotine-Induced Locomotor Sensitization and Nicotine-Enhanced Dopaminergic Activity in Mice. Mar Drugs 23:.
Examples:

TC#NameOrganismal TypeExample
8.B.32.1.1

α-Conotoxin MII of 68 aas and 1 TMS. A number of conopeptides have been developed as analgesics for the treatment of neuropathic pain (Alonso et al. 2003). The 3-d structure has been determined (2AJW_A) (Turner et al. 2009).

α-Conotoxin MII of Conus magus (Magus cone) (Magician's cone snail)

 
8.B.32.1.10

Alpha-conotoxin PIVA of 68 aas and 1 N-terminal TMS. This α-conotoxin acts on postsynaptic membranes, binding to nicotinic acetylcholine receptors (nAChR) and inhibiting them. This toxin has higher affinity for the adult subtype (alpha-1/beta-1/gamma/delta subunits) of the receptor than for the fetal subtype (alpha-1/beta-1/epsilon/delta subunits) (Teichert et al. 2006).

PIVA of Conus purpurascens (Purple cone)

 
8.B.32.1.11

Alpha-conotoxin Lt14.1 of 64 aas and 1 TMS. It is an acetylcholine receptor inhibiting toxin and may impair ion channel function. The protein may be amidated and hydroxylated and possess a disulfide bond (Peng et al. 2006).

α-conotoxin of Conus litteratus (Lettered cone)

 
8.B.32.1.12

ConotoxinEb14.7 of 74 aas and 1 TMS (Liu et al. 2012).

ConotoxinEb14.7 of Conus eburneus

 
8.B.32.1.13

Conotoxin BuIA of 60 aas and 2 TMSs, N- and C-terminal. Alpha-conotoxins bind to the nicotinic acetylcholine receptors (nAChR) and inhibit them (Shiembob et al. 2006). alpha3beta2 nAChR neuronal nicotinic acetylcholine receptors (nAChRs) are pentamers composed of alpha and beta subunits.

 

Conotoxin BuIA of Conus bullatus (Bubble cone)

 
8.B.32.1.14

Alpha-conotoxin TxIB of 41 aas. α-Conotoxin TxIB reverses nicotine-induced locomotor sensitization and nicotine-enhanced dopaminergic activity in mice (Xu et al. 2025).

α-Conotoxin TxIB of Conus textile (Cloth-of-gold cone)

 
8.B.32.1.2

α-Conαotoxin Qc alphaL-1 of 68 aas and 1 TMS.  Alpha-conotoxins act on postsynaptic membranes, binding to the nicotinic acetylcholine receptors (nAChR) and thus inhibiting them. This toxin has 3 cysteine residues in the mature peptide.

α-Conαotoxin Qc alphaL-1 of Conus quercinus (Oak cone)

 
8.B.32.1.3

α-Conotoxin Ac1.1 of 59 aas and 1 TMS. 

α-Conotoxin Ac1.1 of Conus achatinus

 
8.B.32.1.4

α-Conotoxin LvIA of 37 aas and 1 TMS.  This toxin blocks alpha-3-beta-2/CHRNA3-CHRNB2 nAChR with high selectivity (IC50=8.7 nM (on rat) and 17.5 (on human)) (Luo et al. 2014). An alpha 4/7-Conotoxin LvIF from Conus lividus selectively blocks alpha3beta2 nicotinic acetylcholine receptor (Guo et al. 2021). The cryoEM structures are available (5XGL).

 

Alpho-conotoxin of Conus lividus (Livid cone)

 
8.B.32.1.5

Alpha-conotoxin of 63 aas and 1 TMS.

α-conotoxin of Conus praecellens (Admirable cone)

 
8.B.32.1.6

Alpha-conotoxin Pu1.2 of 41 aas and 1 TMS.

α-Conotoxin of Conus pulicarius

 
8.B.32.1.7

Alpha conotoxin GIC of 40 aas and 1 TMS. This toxin reversibly blocks neuronal nAChRs (alpha-3/beta-2 = alpha-6 or -3/beta-2 or -3 > alpha-3/beta-4 = alpha-4/beta-2) (McIntosh et al. 2002).

α-Conotoxin GIC of Conus geographus (Geography cone) (Nubecula geographus)

 
8.B.32.1.8

Alpha-conotoxin-like Leo-A1 of 43 aas and 1 TMS.

Leo-A1 of Conus leopardus (Leopard cone)

 
8.B.32.1.9

Rho-conotoxin of 58 aas.

Rho-conotoxin of Conus tulipa (Fish-hunting cone snail) (Tulip cone)

 
Examples:

TC#NameOrganismal TypeExample
8.B.32.2.1

Kappa-conotoxin Ac4.2 of 41 aas and 1 TMS.  Kappa-conotoxins bind and inhibit voltage-gated potassium channels (Rashid et al. 2013).

κ-Conotoxin of Conus achatinus

 
8.B.32.2.2

Conotoxin Bu26 of 51 aa

Conotoxin of Conus bullatus

 
8.B.32.2.3

Kappa-conotoxin-like Ac4.3a of 52 aa

Kappa-conotoxin-like Ac4.3a of Conus achatinus
 
8.B.32.2.4

PeIVB α-conotoxin of 18 aas. This toxin selectively binds to the fetal (alpha-1/beta-1/gamma/delta subunits) mammalian muscle nicotinic acetylcholine receptors (nAChR) and blocks the elicited currents completely and dissociates very slowly from the fetal muscle receptor (Teichert et al. 2006).

PeIVB of Conus pergrandis (Grand cone)

 
8.B.32.2.5

PIVE conotoxin of 24 aas. This toxin elicits dose-dependent excitatory activity upon injection into fish. Its action is slowly reversible. It does not have effects on the fish potassium channels, TSha1, TSha2 (Kv1 homologs), and Traw (Kv3 homolog) (Teichert et al. 2007).

PIVE conotoxin of Conus purpurascens (Purple cone)