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  • 2005-2009  (2)
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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Stromal cell-derived factor-1α (SDF-1α) is a chemokine whose receptor, CXCR4, is distributed in specific brain areas including hypothalamus. SDF-1α has recently been found to play important roles in neurons, although direct modulation of voltage-gated ionic channels has never been shown. In order to clarify this issue, we performed patch-clamp experiments in fetal mouse hypothalamic neurons in culture. SDF-1α (10 nm) decreased the peak and rising slope of the action potentials and spike discharge frequency in 22% of hypothalamic neurons tested. This effect was blocked by the CXCR4 antagonist AMD 3100 (1 µm) but not by the metabotropic glutamate receptor antagonist MCPG (500 µm), indicating a direct action of SDF-1α on its cognate receptor. This effect involved a depression of both inward and outward voltage-dependent currents of the action potential. We confirmed these effects in the human neuroblastoma cell line SH-SY5Y, which endogenously expresses CXCR4. Voltage-clamp experiments revealed that SDF-1α induced a 20% decrease in the peak of the tetrodotoxin-sensitive sodium current and tetraethylammonium-sensitive delayed rectifier potassium current, respectively. Both effects were concentration dependent, and blocked by AMD 3100 (200 nm). This dual effect was reduced or blocked by 0.4 mm GTPγS G-protein pre-activation or by pre-treatment with the G-protein inhibitor pertussis toxin (200 ng/mL), suggesting that it is mediated via activation of a Gi/o protein. This study extends the functions of SDF-1α to a direct modulation of voltage-dependent membrane currents of neuronal cells.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Stromal cell-derived factor 1α (SDF-1α), a chemoattractant for leucocytes and neurons, and its receptor, CXCR4 are expressed in subsets of neurons of specific brain areas. In rat lateral hypothalamic area (LHA) we show, using immunocytochemistry, that CXCR4 is localized within melanin-concentrating hormone (MCH)-expressing neurons, mainly involved in feeding behaviour regulation. We investigated whether SDF-1α may control MCH neuronal activity. Patch-clamp recordings in rat LHA slices revealed multiple effects of SDF-1α on the membrane potential of MCH neurons, indirect through glutamate/GABA release and direct through GIRK current activation. Moreover, SDF-1α at 0.1–1 nm decreased peak and discharge frequency of action potential evoked by current pulses. These effects were further confirmed in voltage-clamp experiments, SDF-1α depressing both potassium and sodium currents. At 10 nm, however, SDF-1α increased peak and discharge frequency of action potential evoked by current pulses. Using a specific CXCR4 antagonist, we demonstrated that only the depressing effect on AP discharge was mediated through CXCR4 while the opposite effect was indirect. Together, our studies reveal for the first time a direct effect of SDF-1α on voltage-dependent membrane currents of neurons in brain slices and suggest that this chemokine may regulate MCH neuron activity.
    Type of Medium: Electronic Resource
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