title: Synthesis and characterization of a cyclooctapeptide analogue of ω-agatoxin IVB enhancing the activity of Cav2.1 calcium channels activity in cultured hippocampal neurons.
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 (14)Trp is essential for the binding of the neurotoxin to the CaV2.1 VGCC, the substitution of the (12)Cys 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 Ca(2+) 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. In addition, this peptide did not affect cell survival measured with the MTT assay. Therefore, such new cyclopeptidic structures are potential good candidates for synthesis of new agents aimed at the restoration deficient excitatory synaptic transmission.
authors: UMR 5247, Institut des Biomolécules Max Mousseron, CNRS, Université Montpellier 1 & Université Montpellier 2, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
authors: Emilie
authors: E
authors: Pringos
authors: Nadine
authors: N
authors: Crouzin
authors: Mélanie
authors: M
authors: Cavalier
authors: Janique
authors: J
authors: Guiramand
authors: Catherine
authors: C
authors: Cohen-Solal
authors: Jean
authors: J
authors: Martinez
authors: Michel
authors: M
authors: Vignes
authors: Valérie
authors: V
authors: Rolland
mesh_terms: D060848:Agatoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D060848:Agatoxins; D020864:Calcium Channels, N-Type; C083855:omega-agatoxin-Aa4b