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The Journal of Neuroscience, June 6, 2007, 27(23):6302-6312; doi:10.1523/JNEUROSCI.1019-07.2007
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Cellular/Molecular
Inhibition of Resting Potassium Conductances by Long-Term Activation of the NO/cGMP/Protein Kinase G Pathway: A New Mechanism Regulating Neuronal Excitability
David González-Forero,1 Federico Portillo,1,2 Laura Gómez,1 Fernando Montero,1 Sergey Kasparov,2 andBernardo Moreno-López1 1Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, 11003 Cádiz, Spain, and 2Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom
Correspondence should be addressed to Dr. Bernardo Moreno-López, Área de Fisiología, Facultad de Medicina, Plaza Falla 9, 11003 Cádiz, Spain. Email: bernardo.moreno{at}uca.es
Glutamate-induced excitotoxicity, the most common pathological mechanism leading to neuronal death, may occur even with normal levels of glutamate if it coincides with a persistent enhancement of neuronal excitability. Neurons expressing nitric oxide (NO) synthase (NOS-I), which is upregulated in many human chronic neurodegenerative diseases, are highly susceptible to neurodegeneration. We hypothesized that chronic production of NO in damaged neurons may increase their intrinsic excitability via modulation of resting or "leak" K+ currents. Peripheral XIIth nerve injury in adult rats induced de novo NOS-I expression and an increased incidence of low-threshold motor units, the latter being prevented by chronic inhibition of the neuronal NO/cGMP pathway. Accordingly, sustained synthesis of NO maintained an enhanced basal activity in injured motoneurons that was slowly reverted (over the course of 2–3 h) by NOS-I inhibitors. In slice preparations, persistent, but not acute, activation of the NO/cGMP pathway evoked a robust augment in motoneuron excitability independent of synaptic activity. Furthermore, chronic activation of the NO/cGMP pathway fully suppressed TWIK-related acid-sensitive K+ (TASK) currents through a protein kinase G (PKG)-dependent mechanism. Finally, we found evidence for the involvement of this long-term mechanism in regulating membrane excitability of motoneurons, because their pH-sensitive currents were drastically reduced by nerve injury. This NO/cGMP/PKG-mediated modulation of TASK conductances might represent a new pathological mechanism that leads to hyperexcitability and sensitizes neurons to excitotoxic damage. It could explain why de novo expression of NOS-I and/or its overexpression makes them susceptible to neurodegeneration under pathological conditions.
Key words: hypoglossal motoneurons; nerve injury; neuronal excitability; NOS-I upregulation; TASK channels; neurodegenerative diseases
Received May 5, 2006; revised April 18, 2007; accepted April 30, 2007.
Correspondence should be addressed to Dr. Bernardo Moreno-López, Área de Fisiología, Facultad de Medicina, Plaza Falla 9, 11003 Cádiz, Spain. Email: bernardo.moreno{at}uca.es
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