Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
J Biol Chem. 2011 Mar 25;286(12):10233-7. doi: 10.1074/jbc.M110.196170. Epub 2011 Jan 20.
α-Conotoxins are peptides from cone snails that target the nicotinic acetylcholine receptor (nAChR). RgIA and Vc1.1 have analgesic activity in animal pain models. Both peptides target the α9α10 nAChR and inhibit N-type calcium channels via GABA(B) receptor activation, but the mechanism of action of analgesic activity is unknown. PeIA has previously been shown to inhibit the α9α10 and α3β2 nAChRs. In this study, we have determined the structure of PeIA and shown that it is also a potent inhibitor of N-type calcium channels via GABA(B) receptor activation. The characteristic α-conotoxin fold is present in PeIA, but it has a different distribution of surface-exposed hydrophobic and charged residues compared with Vc1.1. Thus, the surface residue distribution, rather than the overall fold, appears to be responsible for the 50-fold increase in selectivity at the α3β2 nAChR by PeIA relative to Vc1.1. In contrast to their difference in potency at the nAChR, the equipotent activity of PeIA and Vc1.1 at the GABA(B) receptor suggests that the GABA(B) receptor is more tolerant to changes in surface residues than is the nAChR. The conserved Asp-Pro-Arg motif of Vc1.1 and RgIA, which is crucial for potency at the α9α10 nAChR, is not required for activity at GABA(B) receptor/N-type calcium channels because PeIA has a His-Pro-Ala motif in the equivalent position. This study shows that different structure-activity relationships are associated with the targeting of the GABA(B) receptor versus nAChRs. Furthermore, there is probably a much more diverse range of conotoxins that target the GABA(B) receptor than currently realized.
α-芋螺毒素是来自芋螺的肽，靶向烟碱型乙酰胆碱受体（nAChR）。RgIA 和 Vc1.1 在动物疼痛模型中具有镇痛活性。这两种肽都靶向α9α10 nAChR，并通过 GABA(B)受体激活抑制 N 型钙通道，但镇痛活性的作用机制尚不清楚。PeIA 先前已被证明抑制α9α10 和α3β2 nAChR。在这项研究中，我们确定了 PeIA 的结构，并表明它也是通过 GABA(B)受体激活抑制 N 型钙通道的有效抑制剂。特征性的α-芋螺毒素折叠存在于 PeIA 中，但与 Vc1.1 相比，它具有不同的表面暴露疏水性和带电残基分布。因此，表面残基分布而不是整体折叠似乎是 PeIA 相对于 Vc1.1 对α3β2 nAChR 选择性增加 50 倍的原因。与它们在 nAChR 上的效力差异相反，PeIA 和 Vc1.1 在 GABA(B)受体上的等效活性表明 GABA(B)受体比 nAChR 更能耐受表面残基的变化。对于 α9α10 nAChR 的效力至关重要的 Vc1.1 和 RgIA 的保守 Asp-Pro-Arg 基序，在 GABA(B)受体/N 型钙通道中不需要活性，因为 PeIA 在等效位置具有 His-Pro-Ala 基序。这项研究表明，与靶向 GABA(B)受体与 nAChRs 相关的结构-活性关系不同。此外，可能有比目前意识到的更多种类的芋螺毒素靶向 GABA(B)受体。
