Conotoxins as Tools to Understand the Physiological Function of Voltage-Gated Calcium (CaV) Channels

Abstract

Voltage-gated calcium (CaV) channels are widely expressed and are essential for the completion of multiple physiological processes. Close regulation of their activity by specific inhibitors and agonists become fundamental to understand their role in cellular homeostasis as well as in human tissues and organs. CaV channels are divided into two groups depending on the membrane potential required to activate them: High-voltage activated (HVA, CaV1.1–1.4; CaV2.1–2.3) and Low-voltage activated (LVA, CaV3.1–3.3). HVA channels are highly expressed in brain (neurons), heart, and adrenal medulla (chromaffin cells), among others, and are also classified into subtypes which can be distinguished using pharmacological approaches. Cone snails are marine gastropods that capture their prey by injecting venom, “conopeptides”, which cause paralysis in a few seconds. A subset of conopeptides called conotoxins are relatively small polypeptides, rich in disulfide bonds, that target ion channels, transporters and receptors localized at the neuromuscular system of the animal target. In this review, we describe the structure and properties of conotoxins that selectively block HVA calcium channels. We compare their potency on several HVA channel subtypes, emphasizing neuronal calcium channels. Lastly, we analyze recent advances in the therapeutic use of conotoxins for medical treatments.

Ion Channel Function During Oocyte Maturation and Fertilization

“…Ca v 1.1–1.4 (L-type current) and Ca v 2.1–2.3 (P/Q, N, and R type) belong to the HVA group, while Ca v 3.1–3.3 (T-type current) to the LVA group. Between other functions, voltage-gated Ca 2+ channels are responsible for initiation of synaptic transmission, hormone secretion, and excitation-contraction coupling (Hille, 2001 ; Catterall, 2011 ; Ramirez et al, 2017 ).…”

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

“…The classification of knottins is based on criteria such as the gene superfamily, the pattern of cysteine bridging, and molecular targets [33,39]. ERVK CTXLP most resembles O-conotoxins (which encompass ω and γ conotoxin groups); these small toxic peptides act by blocking ion channels [40]. Inhibition of high-voltage activated Ca V 2.2 (N-type) calcium channels found at the presynaptic terminal of neurons by O-conotoxins, leads to suppressed acetylcholine release and neurotransmission [41].…”

“…Inhibition of high-voltage activated Ca V 2.2 (N-type) calcium channels found at the presynaptic terminal of neurons by O-conotoxins, leads to suppressed acetylcholine release and neurotransmission [41]. The success of piscivorous cone snails to envenomate and immobilize their prey by blocking neuromuscular transmission is attributed to the efficacy of conotoxin peptides [34,40].…”

Discovery Methodology of Novel Conotoxins from Conus Species

“…Early studies have confirmed that these bioactive venoms are a cocktail of neuroactive peptides, termed conopeptides or conotoxins, which can cause paralysis, shudder, and even death of the prey within seconds [ 1 , 5 ]. Subsequent research have revealed that conopeptides are able to selectively modulate voltage-gated ion channels [ 7 ] ( Table 1 ), including sodium channels [ 8 , 9 ], potassium channels [ 10 ], and calcium channels [ 11 , 12 ], as well as ligand-gated ion channels ( Table 1 ), such as nAChRs [ 13 , 14 , 15 ], serotonin receptor [ 16 ], NMDA receptor [ 17 ], GABA receptor [ 18 ], GPCRs [ 19 ] (α 1 -adrenoceptors [ 20 , 21 ], vasopressin receptor [ 22 ], neurotensin receptor [ 23 ]), and neurotransmitter transporters (noradrenaline transporter [ 21 , 24 ]), which are key targets for chronic diseases, like neuralgia [ 8 , 25 , 26 ], addiction [ 27 ], epilepsy [ 17 , 28 ], cancer [ 29 ], heart disease [ 30 , 31 ], and so on [ 32 , 33 , 34 ].…”