title: Beta-amyloid enhances intracellular calcium rises mediated by repeated activation of intracellular calcium stores and nicotinic receptors in acutely dissociated rat basal forebrain neurons.
abstract: Beta-amyloid, a 39-43 amino acid peptide, may exert its biological effects via neuronal nicotinic acetylcholine receptors. Using the ratiometric dye, fura-2, we examined the effect of soluble beta-amyloid(1-42) on the concentration of intracellular Ca(2+) ([Ca(2+)](i)) in acutely dissociated rat basal forebrain neurons. Focal applications of nicotine (0.5-20 mM), evoked dose-dependent increases in intracellular [Ca(2+)](i) that were mediated by the entry of extracellular Ca(2+) via nicotinic acetylcholine receptors, and the release of intracellular Ca(2+) from stores. With repeated nicotine challenges, the nicotinic responses were potentiated by 98 +/- 12% (P < 0.05) while beta-amyloid(1-42)(100 nM) was present for approximately 5 min. This potentiation became larger during the subsequent washout of beta-amyloid(1-42), which was associated with a gradual rise in baseline [Ca(2+)](i). Application of beta-amyloid(1-42)by itself did not alter [Ca(2+)](i), and beta-amyloid(1-42)also had no significant effect on the response to repeated KCl challenges. Therefore, beta-amyloid(1-42) caused neither gross disturbance of cellular Ca(2+) homeostasis nor enhancement of voltage-gated Ca(2+) channels. Interestingly, beta-amyloid(1-42) transiently potentiated the response to repeated caffeine challenges, which was also associated with a transient rise in baseline [Ca(2+)](i). beta-amyloid(1-42) potentiation of nicotine-evoked rises in [Ca(2+)](i) was reversed by the SERCA pump inhibitor, thapsigargin, and the mitochondrial Na(+)/Ca(2+) exchanger inhibitor, CGP-37157. These results suggest that the dysregulation of [Ca(2+)](i) by beta-amyloid(1-42) during multiple challenges with nicotine or caffeine involved the sensitization or overfilling of intracellular stores that are maintained by SERCA pump and Ca(2+) efflux from the mitochondria.
authors.affiliation: Department of Medicine, Division of Neurology, University of Alberta, 530 Heritage Medical Research Centre, Edmonton, AB, Canada T6G 2S2.
authors.forename: James H
authors.initials: JH
authors.lastname: Chin
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Tse
authors.forename: Kim
authors.initials: K
authors.lastname: Harris
authors.forename: Jack H
authors.initials: JH
authors.lastname: Jhamandas
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D016257:Fura-2; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C506945:Atp2a1 protein, rat; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C075222:amyloid beta-protein (1-42); D002110:Caffeine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000109:Acetylcholine; D002118:Calcium; D016257:Fura-2