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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Synthesis and characterization of a cyclooctapeptide analogue of ω-agatoxin IVB enhancing the activity of CaV2.1 calcium channels activity in cultured hippocampal neurons
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Synthesis and characterization of a cyclooctapeptide analogue of ω-agatoxin IVB enhancing the activity of CaV2.1 calcium channels activity in cultured hippocampal neurons

机译：ω-agatoxinIVB环八肽类似物的合成和表征，可增强培养的海马神经元中CaV2.1钙通道的活性

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摘要

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 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.
机译：考虑到主要涉及P / Q型（CaV2.1）电压的突触传递调制器的设计，从漏斗网蜘蛛Agelenopsis aperta的毒液中提取的毒素ω-agatoxinIVB的结构是重要的铅结构。门控钙通道（VGCC）在中央突触。着眼于似乎是毒素与CaV2.1 VGCC最重要的相互作用域的ω-毒素IVB的环2，合成了模拟该环的环八肽。虽然14Trp对于神经毒素与CaV2.1 VGCC的结合至关重要，但是用12Cys取代缩水甘油基残基会导致名为EP14的环八肽，该环八肽能够增强用膜片钳记录法测量的与CaV2.1 VGCC相关的电流，并且如呋喃2分光荧光成像所测得的，引起ω-抗毒素IVA敏感的细胞内Ca 2+增加。此外，该环八肽能够在培养的海马神经元网络中增强自发性兴奋性突触传递，这与EP14激活突触前VGCC一致。另外，该肽不影响用MTT测定法测量的细胞存活。因此，这种新的环肽结构是合成旨在恢复缺乏的兴奋性突触传递的新药剂的潜在良好候选者。

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