Huidobro-Toro J Pablo, Lorca Ramón A, Coddou Claudio
Laboratorio de Nucleótidos, Centro de Regulación Celular y Patología, JV Luco, Instituto Milenio MIFAB, Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Eur Biophys J. 2008 Mar;37(3):301-14. doi: 10.1007/s00249-007-0230-7. Epub 2007 Oct 31.
Zinc and copper are indispensable trace metals for life with a recognized role as catalysts in enzyme actions. We now review evidence supporting the role of trace metals as novel allosteric modulators of ionotropic receptors: a new and fundamental physiological role for zinc and copper in neuronal and brain excitability. The review is focussed on ionotropic receptor channels including nucleotide receptors, in particular the P2X receptor family. Since zinc and copper are stored within synaptic vesicles in selected brain regions, and released to the synaptic cleft upon electrical nerve ending depolarization, it is plausible that zinc and copper reach concentrations in the synapse that profoundly affect ligand-gated ionic channels, including the ATP-gated currents of P2X receptors. The identification of key P2X receptor amino acids that act as ligands for trace metal coordination, carves the structural determinants underlying the allosteric nature of the trace metal modulation. The recognition that the identified key residues such as histidines, aspartic and glutamic acids or cysteines in the extracellular domain are different for each P2X receptor subtype and may be different for each metal, highlights the notion that each P2X receptor subtype evolved independent strategies for metal coordination, which form upon the proper three-dimensional folding of the receptor channels. The understanding of the molecular mechanism of allosteric modulation of ligand-operated ionic channels by trace metals is a new contribution to metallo-neurobiology.
锌和铜是生命中不可或缺的微量金属，在酶促反应中作为催化剂发挥着公认的作用。我们现在回顾支持微量金属作为离子型受体新型变构调节剂作用的证据：锌和铜在神经元和大脑兴奋性方面具有新的基本生理作用。本综述聚焦于离子型受体通道，包括核苷酸受体，特别是P2X受体家族。由于锌和铜储存在特定脑区的突触小泡中，并在神经末梢去极化时释放到突触间隙，锌和铜在突触中达到能深刻影响配体门控离子通道（包括P2X受体的ATP门控电流）的浓度是合理的。确定作为微量金属配位配体的关键P2X受体氨基酸，揭示了微量金属调节变构性质背后的结构决定因素。认识到细胞外结构域中已确定的关键残基（如组氨酸、天冬氨酸、谷氨酸或半胱氨酸）在每种P2X受体亚型中不同，且可能因每种金属而异，突出了这样一种观念，即每种P2X受体亚型都进化出了独立的金属配位策略，这些策略在受体通道正确的三维折叠时形成。对微量金属对配体操作离子通道变构调节分子机制的理解是对金属神经生物学的新贡献。
