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Received August 1, 2002
Accepted after revision October 2, 2002
1 Department of Pharmacology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
2 Department of Pharmacology & Neuroscience, Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY, UK
* To whom correspondence should be addressed. E-mail: j.z.harvey{at}dundee.ac.uk.
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 neurons via activation of large conductance Ca2+-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 Ca2+ levels evoked following Mg2+ removal in hippocampal cultures. The ability of leptin to modulate this activity required activation of BK, but not KATP, 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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