Calcium mobilising pathways and Δψm in striatal progenitor cells

• Type: International Conference Proceedings Book
• Date: 2004

Authors

Jorge M.A. Oliveira (Author) FFUP; Almeida S (Author) Other; Domingues A (Author) Other; Ellerby LM (Author) Other; Gonçalves J (Author) Other; Oliveira CR (Author) Other; Rego AC (Author) Other

Publisher

Fundamental and Clinical Pharmacology

Conference International

EPHAR 2004

Porto, Portugal, 2004

Indexing

ISI Web of Science

Scientific classification

FOS: Medical and Health sciences > Health sciences

CORDIS: Health sciences > Pharmacological sciences ; Health sciences > Neuroscience > Neurochemistry ; Health sciences > Neuroscience > Neurophysiology

Other information

Resumo (PT): Huntington's disease (HD) is an inherited neurodegenerative disorder known to be caused by a mutant form of the huntingtin (Htt) protein. However, the detailed mechanisms through which Htt exerts its deleterious effects, as well as the reasons for the selective striatal degeneration in HD, are currently unknown. Immortalised striatal progenitor cells from knock-in mice, expressing either normal (STQ7) or mutant (STQ111) Htt, have been pointed out as putative early models of HD. With the aim of studying changes in calcium homeostasis we probed these cells for multiple Ca2+ mobilising receptors. We observed metabotropic Ca2+ responses to ATP and histamine. Despite positive immunolabelling of N-methyl-D-aspartate (NMDA) receptor subunits, Ca2+-responses to NMDA were only observed when the cells were transfected with expression plasmids encoding these receptor subunits. Nevertheless, even at maximal receptor activation, none of these agonist-evoked Ca2+ rises were sufficient to induce mitochondrial depolarisation, as assessed through simultaneous imaging of Ca2+ and mitochondrial membrane potential (Δψm), respectively, with Fura2 and Rhodamine-123 (Rh123) in single cells. Nevertheless, we observed a lower Rh123 peak response to oligomycin plus FCCP in untreated STQ111, as compared to STQ7, indicating basal differences in Δψm and thus positioning mitochondrial dysfunction as an early event in HD.

Abstract (EN): Huntington's disease (HD) is an inherited neurodegenerative disorder known to be caused by a mutant form of the huntingtin (Htt) protein. However, the detailed mechanisms through which Htt exerts its deleterious effects, as well as the reasons for the selective striatal degeneration in HD, are currently unknown. Immortalised striatal progenitor cells from knock-in mice, expressing either normal (STQ7) or mutant (STQ111) Htt, have been pointed out as putative early models of HD. With the aim of studying changes in calcium homeostasis we probed these cells for multiple Ca2+ mobilising receptors. We observed metabotropic Ca2+ responses to ATP and histamine. Despite positive immunolabelling of N-methyl-D-aspartate (NMDA) receptor subunits, Ca2+-responses to NMDA were only observed when the cells were transfected with expression plasmids encoding these receptor subunits. Nevertheless, even at maximal receptor activation, none of these agonist-evoked Ca2+ rises were sufficient to induce mitochondrial depolarisation, as assessed through simultaneous imaging of Ca2+ and mitochondrial membrane potential (Δψm), respectively, with Fura2 and Rhodamine-123 (Rh123) in single cells. Nevertheless, we observed a lower Rh123 peak response to oligomycin plus FCCP in untreated STQ111, as compared to STQ7, indicating basal differences in Δψm and thus positioning mitochondrial dysfunction as an early event in HD.

Language: Portuguese

Type (Professor's evaluation): Scientific