title: Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins.
abstract: Zinc is an essential metal to life. This transition metal is a structural component of many proteins and is actively involved in the catalytic activity of cell enzymes. In either case, these zinc-containing proteins are metalloproteins. However, the amino acid residues that serve as ligands for metal coordination are not necessarily the same in structural proteins compared to enzymes. While crystals of structural proteins that bind zinc reveal a higher preference for cysteine sulfhydryls rather than histidine imidazole rings, catalytic enzymes reveal the opposite, i.e., a greater preference for the histidines over cysteines for catalysis, plus the influence of carboxylic acids. Based on this paradigm, we reviewed the putative ligands of zinc in ionotropic receptors, where zinc has been described as an allosteric modulator of channel receptors. Although these receptors do not strictly qualify as metalloproteins since they do not normally bind zinc in structural domains, they do transitorily bind zinc at allosteric sites, modifying transiently the receptor channel's ion permeability. The present contribution summarizes current information showing that zinc allosteric modulation of receptor channels occurs by the preferential metal coordination to imidazole rings as well as to the sulfhydryl groups of cysteine in addition to the carboxyl group of acid residues, as with enzymes and catalysis. It is remarkable that most channels, either voltage-sensitive or transmitter-gated receptor channels, are susceptible to zinc modulation either as positive or negative regulators.
authors.affiliation: Laboratorio de Farmacolog&#237;a de Nucle&#243;tidos, Laboratorio de Farmacolog&#237;a, Departamento de Biolog&#237;a, Facultad de Qu&#237;mica y Biolog&#237;a, y Centro para el Desarrollo de Nanociencias y Nanotecnolog&#237;a (CEDENNA), Universidad de Santiago de Chile, Alameda Libertador B. O'Higgins, 3363 Santiago, Chile. francisco.andres.peralta@gmail.com.
authors.forename: Francisco Andrés
authors.initials: FA
authors.lastname: Peralta
authors.affiliation: Laboratorio de Farmacolog&#237;a de Nucle&#243;tidos, Laboratorio de Farmacolog&#237;a, Departamento de Biolog&#237;a, Facultad de Qu&#237;mica y Biolog&#237;a, y Centro para el Desarrollo de Nanociencias y Nanotecnolog&#237;a (CEDENNA), Universidad de Santiago de Chile, Alameda Libertador B. O'Higgins, 3363 Santiago, Chile. juan.garcia-huidobro@usach.cl.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Huidobro-Toro
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D006801:Humans; D058446:Ligand-Gated Ion Channels / Q000737:chemistry* / Q000378:metabolism; D008667:Metalloproteins / Q000737:chemistry* / Q000378:metabolism; D000072417:Protein Domains; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D058446:Ligand-Gated Ion Channels; D008667:Metalloproteins; D015032:Zinc
keywords: protein zinc ligands; zinc allosteric modulator; zinc and ionotropic receptors; zinc coordination; zinc coordination sphere; zinc-activated channel