title: Amyloid β peptide (25-35) in picomolar concentrations modulates the function of glycine receptors in rat hippocampal pyramidal neurons through interaction with extracellular site(s).
abstract: β-Amyloid peptide (Aβ) plays a central role in the pathogenesis of Alzheimer׳s disease, but in lower amounts it is found in normal brains where it participates in physiological processes and probably regulates synaptic plasticity. This study investigated the effects of physiologically relevant concentrations of Aβ (1 pM-100 nM), fragment 25-35, on glycine-mediated membrane current in acutely isolated rat hippocampal pyramidal neurons using whole-cell patch-clamp technique. We have found that short (600 ms) co-application of glycine with Aβ caused reversible dose-dependent and voltage-independent acceleration of desensitization of glycine current. The peak amplitude of the current remained unchanged. The effect of picomolar Aβ concentrations persisted in the presence of 1 µM Aβ in the pipette solution, implying that Aβ bounds to extracellular site(s). Concentration-dependence curve was N-shaped with maximums at 100 pM and 100 nM, suggesting the existence of two binding sites, which may interact with each other. Glycine current resistant to 100 µM picrotoxin, was insensitive to Aβ, which suggests that Aβ affected mainly homomeric glycine receptors. When Aβ was added to bath solution, besides acceleration of desensitization, it caused reversible dose-dependent reduction of glycine current peak amplitude. These results demonstrate that physiological (picomolar) concentrations of Aβ reversibly augment the desensitization of glycine current, probably by binding to external sites on homomeric glycine receptors. Furthermore, Aβ can suppress the peak amplitude of glycine current, but this effect develops slowly and may be mediated through some intracellular machinery.
authors.affiliation: Brain Research Department, Research Center of Neurology, Russian Academy of Medical Sciences, Per. Obukha 5, Moscow 105064, Russia. Electronic address: bukanovaj@mail.ru.
authors.forename: J V
authors.initials: JV
authors.lastname: Bukanova
authors.affiliation: Brain Research Department, Research Center of Neurology, Russian Academy of Medical Sciences, Per. Obukha 5, Moscow 105064, Russia. Electronic address: sharonova.irina@gmail.com.
authors.forename: I N
authors.initials: IN
authors.lastname: Sharonova
authors.affiliation: Brain Research Department, Research Center of Neurology, Russian Academy of Medical Sciences, Per. Obukha 5, Moscow 105064, Russia. Electronic address: skrebitsky@yahoo.com.
authors.forename: V G
authors.initials: VG
authors.lastname: Skrebitsky
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000187:drug effects*; D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000187:drug effects*; D010852:Picrotoxin / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000378:metabolism*; D013331:Strychnine / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D001640:Bicuculline; D018756:GABA Antagonists; D018684:Glycine Agents; D010446:Peptide Fragments; D010852:Picrotoxin; D018009:Receptors, Glycine; D013331:Strychnine; C074636:amyloid beta-protein (25-35); C017069:bicuculline methiodide
keywords: Desensitization; Glycine receptor; Pyramidal neurons; Rat hippocampus; Whole-cell patch clamp; β-amyloid