Abstract
The structure of the toxin ω-agatoxin IVB, extracted from the venom of funnel-web spider Agelenopsis Aperta, is an important lead structure when considering the design of modulators of synaptic transmission which largely involves P/Q-type (Cav2.1) voltage gated calcium channels (VGCC) at central synapses. Focusing on the loop 2 of the ω-agatoxin IVB that seems to be the most preeminent interacting domain of the toxin with the Cav2.1 VGCC, cyclooctapeptides mimicking this loop were synthesized. While 14Trp is essential for the binding of the neurotoxin to the Cav2.1 VGCC, the substitution of the 12Cys for a glycidyl residue led to a cyclooctapeptide named EP14 able to enhance Cav2.1 VGCC-associated currents measured with patch-clamp recordings and to evoke ω-agatoxin IVA-sensitive intracellular Ca2+ increase as measured by fura-2 spectrofluoroimaging. Furthermore, this cyclooctapeptide was able to potentiate spontaneous excitatory synaptic transmission in a network of cultured hippocampal neurons, consistent with the activation of presynaptic VGCC by EP14.