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| Research article summary (published 13 Dec 2002): |
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Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels.
Full Abstract
The obese gene product, leptin is an important circulating satiety factor that regulates energy balance via its actions in the hypothalamus. However, leptin receptors are also expressed in brain regions not directly associated with energy homeostasis, such as the hippocampus. Here, leptin inhibits hippocampal neurones via activation of large conductance Ca(2+)-activated K(+) (BK) channels, a process that may be important in regulating neuronal excitability. We now show that leptin receptor labelling is expressed on somata, dendrites and axons, and is also concentrated at synapses in hippocampal cultures. In functional studies, leptin potently and reversibly reduces epileptiform-like activity evoked in lean, but not leptin-resistant Zucker fa/fa rats. Furthermore, leptin also depresses enhanced Ca(2+) levels evoked following Mg(2+) removal in hippocampal cultures. The ability of leptin to modulate this activity requires activation of BK, but not K(ATP), channels as the effects of leptin were mimicked by the BK channel activator NS-1619, and inhibited by the BK channel inhibitors, iberiotoxin and charybdotoxin. The signalling mechanisms underlying this process involve stimulation of phosphoinositide 3-kinase (PI 3-kinase), but not mitogen-activated protein kinase (MAPK), as two structurally unrelated inhibitors of PI 3-kinase, LY294002 and wortmannin, blocked the actions of leptin. These data indicate that leptin, via PI 3-kinase-driven activation of BK channels, elicits a novel mechanism for controlling neuronal excitability. As uncontrolled excitability in the hippocampus is one underlying cause of temporal lobe epilepsy, this novel action of leptin could provide an alternative therapeutic target in the management of epilepsy.
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Author information
Author/s: Shanley, L J (LJ); O'Malley, D (D); Irving, A J (AJ); Ashford, M L (ML); Harvey, J (J);
Affiliation: Department of Pharmacology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.
Journal and publication information
Publication Type: Journal Article; Research Support, Non-U.S. Gov't
Journal: The Journal of physiology (J Physiol), published in England. (Language: eng)
Reference: 2002-Dec; vol 545 (issue Pt 3) : pp 933-44
Dates: Created 2002/12/16; Completed 2003/07/02; Revised 2007/11/15;
PMID: 12482897, status: MEDLINE (last retrieval date: 11/6/2008)
Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.
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