Sci. STKE, 6 June 2006
NEUROSCIENCE Neurons Napping After Lunch
Increased extracellular glucose inhibits the electrical activity of hypothalamic orexin- and hypocretin-expressing neurons (orexin neurons) involved in regulating states of consciousness, metabolic rate, and appetite. However, the molecular mechanisms involved--and physiological relevance--have been unclear (see Scott et al.). Burdakov et al. performed whole-cell patch-clamp analysis on orexin neurons in brain slices from transgenic mice that selectively expressed enhanced green fluorescent protein in orexin neurons and found that spontaneous electrical activity was inhibited when extracellular glucose concentration was changed from 0.2 mM to 4.5 mM. Even moderate increases in glucose concentration (from 1 mM to 2.5 mM), consistent with fluctuations in interstitial brain glucose that occur between meals, were sufficient to hyperpolarize orexin neurons and decrease their firing rate. A combination of ion substitution, lack of sensitivity to intracellular calcium concentration, and biophysical analysis indicated that glucose activated a potassium leak channel; the effects of halothane and extracellular acidification implicated the TASK (TWIK-related acid-sensitive K+ channel) family of two-pore-domain potassium channels (TASK K2p). Single-channel analysis of channel biophysical properties and sensitivity to pH, and their insensitivity to ruthenium red, suggested that the channels were heteromers containing TASK3 subunits, a conclusion supported by immunocytochemical analysis. Inhibition of orexin neurons did not depend on glucose entry, changes in intracellular calcium, or changes in intracellular ATP. Thus, the authors have identified a previously unknown mechanism whereby hypothalamic neurons respond to physiologically relevant fluctuations in extracellular glucose.
D. Burdakov, L. T. Jensen, H. Alexopoulos, R. H. Williams, I. M. Fearon, I. O'Kelly, O. Gerasimenko, L. Fugger, A. Verkhratsky, Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron 50, 711-722 (2006). [PubMed]
M. M. Scott, J. N. Marcus, J. K. Elmquist, Orexin neurons and the TASK of glucosensing. Neuron 50, 665-667 (2006). [PubMed]
Citation: Neurons Napping After Lunch. Sci. STKE 2006, tw188 (2006).
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