Peptide Neurotoxins That Affect Voltage-Gated Calcium Channels: A Close-Up on ω-Agatoxins

Abstract

Peptide neurotoxins found in animal venoms have gained great interest in the field of neurotransmission. As they are high affinity ligands for calcium, potassium and sodium channels, they have become useful tools for studying channel structure and activity. Peptide neurotoxins represent the clinical potential of ion-channel modulators across several therapeutic fields, especially in developing new strategies for treatment of ion channel-related diseases. The aim of this review is to overview the latest updates in the domain of peptide neurotoxins that affect voltage-gated calcium channels, with a special focus on ω-agatoxins.

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

“…There are five different types of VDCCs; members 6 of the L-type (or "Long Lasting") group of Ca 2+ channels contain one of the CaV1.1, CaV1.2, CaV1.3, or CaV1.4 α1 subunits; the N-type ("Neural") contains CaV2.1; the P/Q-type ("Purkinje") contains CaV2.2; the R-type ("Residual") contains CaV2.3; and members of the Ttype ("Transient") group contain CaV3.1, CaV3.2, or CaV3.3 α1 subunits (Table 1) [14,15]. It is of note that the L, N, P/Q and R-type calcium channels are activated at high voltage (HVA), while T-type calcium channels are activated at negative resting membrane potential (RMP) values and are considered as members of the low voltage-activated (LVA) family [16].…”

“…The phenyl-alkylamine verapamil, another potent calcium antagonist, binds to a distinct site on the ion channel and is also widely used as an antihypertensive drug [18]. The L-type channels are sensitive to the neurotoxin calciseptine, in addition to the conventional blockers [16]. The main modulators of N-type calcium channels are ω-conotoxins; P/Q-type channels are selectively blocked by ω-agatoxins; and the peptide neurotoxin SNX-482 is a selective R-type calcium channel inhibitor.…”

Structural Analogy — Direct Similarity Versus Topographical Complementarity

“…Therefore, constrained cyclic analogues with three-dimensional arrangement corresponding to the native structure of the loop were designed (Figure 20). The neurophysiological experiments confirmed the proper choice of the mimetics and the necessity of the presence of properly directed tryptophan (an amino acid fundamental for activity) residue for toxin-channel interactions [56,57]. The synthesized agonists might be useful for the development of treatment for patients with calcium like migraine, related to decreased calcium influx.…”

From Foe to Friend: Using Animal Toxins to Investigate Ion Channel Function

“…The most relevant member of the ω-agatoxin family 133 is IVA, a gating modifier toxin isolated from the funnel-web spider Agelenopsis aperta . IVA is specific for P/Q-type channels and it has been used to isolate P-currents in Purkinje neurons 134; 135 and Q-currents (also with ω-conotoxin MVIIC 136 ) in granular cerebellar neurons 137; 138; 139 .…”