title: Hyperekplexia phenotype of glycine receptor alpha1 subunit mutant mice identifies Zn(2+) as an essential endogenous modulator of glycinergic neurotransmission.
abstract: Zn(2+) is thought to modulate neurotransmission by affecting currents mediated by ligand-gated ion channels and transmitter reuptake by Na(+)-dependent transporter systems. Here, we examined the in vivo relevance of Zn(2+) neuromodulation by producing knockin mice carrying the mutation D80A in the glycine receptor (GlyR) alpha1 subunit gene (Glra1). This substitution selectively eliminates the potentiating effect of Zn(2+) on GlyR currents. Mice homozygous for Glra1(D80A) develop a severe neuromotor phenotype postnatally that resembles forms of human hyperekplexia (startle disease) caused by mutations in GlyR genes. In spinal neurons and brainstem slices from Glra1(D80A) mice, GlyR expression, synaptic localization, and basal glycinergic transmission were normal; however, potentiation of spontaneous glycinergic currents by Zn(2+) was significantly impaired. Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn(2+) potentiation of alpha1 subunit containing GlyRs, indicating that synaptic Zn(2+) is essential for proper in vivo functioning of glycinergic neurotransmission.
authors.affiliation: Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, Deutschordenstrasse 46, 60528 Frankfurt am Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Hirzel
authors.forename: Ulrike
authors.initials: U
authors.lastname: Müller
authors.forename: A Tobias
authors.initials: AT
authors.lastname: Latal
authors.forename: Swen
authors.initials: S
authors.lastname: Hülsmann
authors.forename: Joanna
authors.initials: J
authors.lastname: Grudzinska
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Heinrich
authors.initials: H
authors.lastname: Betz
authors.forename: Bodo
authors.initials: B
authors.lastname: Laube
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D002678:Chimera; D004195:Disease Models, Animal; D020821:Dystonic Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004525:Efferent Pathways / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008818:Mice, Neurologic Mutants; D009154:Mutation; D009433:Neural Inhibition / Q000235:genetics; D009924:Organ Culture Techniques; D010641:Phenotype; D018009:Receptors, Glycine / Q000187:drug effects / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C000657604:GLRA1 protein, human; C000657605:Glra1 protein, mouse; D018009:Receptors, Glycine; D015032:Zinc; D005998:Glycine